Natasha Stevens

Double-blind randomised controlled trial of percutaneous tibial nerve stimulation versus sham electrical stimulation in the treatment of faecal incontinence: CONtrol of Faecal Incontinence using Distal NeuromodulaTion (the CONFIDeNT trial)

BACKGROUND Faecal incontinence (FI) is a common condition which is often under-reported. It is distressing for those suffering from it, impacting heavily on their quality of life. When conservative strategies fail, treatment options are limited. Percutaneous tibial nerve stimulation (PTNS) is a minimally invasive outpatient treatment, shown in preliminary case series to have significant effectiveness; however, no randomised controlled trial has been conducted. OBJECTIVES To assess the effectiveness of PTNS compared with sham electrical stimulation in the treatment of patients with FI in whom initial conservative strategies have failed. DESIGN Multicentre, parallel-arm, double-blind randomised (1 : 1) controlled trial. SETTING Eighteen UK centres providing specialist nurse-led (or equivalent) treatment for pelvic floor disorders. PARTICIPANTS Participants aged > 18 years with FI who have failed conservative treatments and whose symptoms are sufficiently severe to merit further intervention. INTERVENTIONS PTNS was delivered via the Urgent(®) PC device (Uroplasty Limited, Manchester, UK), a hand-held pulse generator unit, with single-use leads and fine-needle electrodes. The needle was inserted near the tibial nerve on the right leg adhering to the manufacturers protocol (and specialist training). Treatment was for 30 minutes weekly for a duration of 12 treatments. Validated sham stimulation involved insertion of the Urgent PC needle subcutaneously at the same site with electrical stimulation delivered to the distal foot using transcutaneous electrical nerve stimulation. MAIN OUTCOME MEASURES Outcome measures were assessed at baseline and 2 weeks following treatment. Clinical outcomes were derived from bowel diaries and validated, investigator-administered questionnaires. The primary outcome classified patients as responders or non-responders, with a responder defined as someone having achieved ≥ 50% reduction in weekly faecal incontinence episodes (FIEs). RESULTS In total, 227 patients were randomised from 373 screened: 115 received PTNS and 112 received sham stimulation. There were 12 trial withdrawals: seven from the PTNS arm and five from the sham arm. Missing data were multiply imputed. For the primary outcome, the proportion of patients achieving a ≥ 50% reduction in weekly FIEs was similar in both arms: 39 in the PTNS arm (38%) compared with 32 in the sham arm (31%) [odds ratio 1.28, 95% confidence interval (CI) 0.72 to 2.28; p = 0.396]. For the secondary outcomes, significantly greater decreases in weekly FIEs were observed in the PTNS arm than in the sham arm (beta -2.3, 95% CI -4.2 to -0.3; p = 0.02), comprising a reduction in urge FIEs (p = 0.02) rather than passive FIEs (p = 0.23). No significant differences were found in the St Marks Continence Score or any quality-of-life measures. No serious adverse events related to treatment were reported. CONCLUSIONS PTNS did not show significant clinical benefit over sham electrical stimulation in the treatment of FI based on number of patients who received at least a 50% reduction in weekly FIE. It would be difficult to recommend this therapy for the patient population studied. Further research will concentrate on particular subgroups of patients, for example those with pure urge FI. TRIAL REGISTRATION Current Controlled Trials ISRCTN88559475. FUNDING This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 19, No. 77. See the NIHR Journals Library website for further project information.

Double-blind randomised controlled trial of vitamin D3 supplementation for the prevention of acute respiratory infection in older adults and their carers (ViDiFlu)

Rationale Low-dose vitamin D supplementation is already recommended in older adults for prevention of fractures and falls, but clinical trials investigating whether higher doses could provide additional protection against acute respiratory infection (ARI) are lacking. Objective To conduct a clinical trial of high-dose versus low-dose vitamin D3 supplementation for ARI prevention in residents of sheltered-accommodation housing blocks (‘schemes’) and their carers in London, UK. Measurements and methods Fifty-four schemes (137 individual participants) were allocated to the active intervention (vitamin D3 2.4 mg once every 2 months +10 μg daily for residents, 3 mg once every 2 months for carers), and 54 schemes with 103 participants were allocated to control (placebo once every 2 months +vitamin D3 10 μg daily for residents, placebo once every 2 months for carers) for 1 year. Primary outcome was time to first ARI; secondary outcomes included time to first upper/lower respiratory infection (URI/LRI, analysed separately), and symptom duration. Main results Inadequate vitamin D status was common at baseline: 220/240 (92%) participants had serum 25(OH)D concentration <75 nmol/L. The active intervention did not influence time to first ARI (adjusted HR (aHR) 1.18, 95% CI 0.80 to 1.74, p=0.42). When URI and LRI were analysed separately, allocation to the active intervention was associated with increased risk of URI (aHR 1.48, 95% CI 1.02 to 2.16, p=0.039) and increased duration of URI symptoms (median 7.0 vs 5.0 days for active vs control, adjusted ratio of geometric means 1.34, 95% CI 1.09 to 1.65, p=0.005), but not with altered risk or duration of LRI. Conclusions Addition of intermittent bolus-dose vitamin D3 supplementation to a daily low-dose regimen did not influence risk of ARI in older adults and their carers, but was associated with increased risk and duration of URI. Trial registration number clinicaltrials.gov NCT01069874.

S123 Increased risk of upper respiratory infection with addition of intermittent bolus-dose vitamin D supplementation to a daily low-dose regimen

Introduction and Objectives Meta-analysis of clinical trials of vitamin D supplementation for the prevention of acute respiratory infection (ARI) shows a protective effect in the general population, but there is controversy regarding the optimal dosing regimen. Low-dose vitamin D supplementation is already recommended in older adults for prevention of fractures and falls, but clinical trials investigating whether higher doses could provide additional protection against ARI are lacking. Methods We conducted a double-blind cluster-randomised placebo-controlled trial of high- vs. low-dose vitamin D supplementation in residents and staff of sheltered accommodation schemes in London, UK. 108 schemes were allocated to receive the intervention (vitamin D3 2.4 mg 2-monthly + 10 μg daily for residents; 3 mg 2-monthly for staff) or control (vitamin D3 10 μg daily for residents, nil for staff) over the course of one year. The primary endpoint of the trial was time from first dose of study medication to date of first ARI, determined by a validated acute respiratory symptom score recorded prospectively in a symptom diary. Secondary outcomes included time to first upper / lower respiratory infections (URI/LRI) and mean serum 25-hydroxyvitamin D (25[OH]D) concentration. Results 240 participants were included in the intention-to-treat analysis (137 participants in 54 schemes allocated to intervention, mean baseline 25[OH]D 43.8 nmol/L vs. 103 participants in 54 schemes allocated to control, mean baseline 25[OH]D 43.8 nmol/L). Median time to ARI was 203 days in the intervention arm and 227 days in the control arm (adjusted HR 1.18, 95% CI 0.80 to 1.74, p = 0.42). Allocation to the intervention arm of the trial was associated with increased risk of URI (adjusted HR 1.48, 95% CI 1.02 to 2.16, p = 0.04), but not with altered risk of LRI (adjusted HR 1.12, 95% CI 0.73 to 1.70, p = 0.61). Mean serum 25(OH)D concentration at 1 year was 84.8 nmol/L vs. 58.5 nmol/L in intervention vs. control arms (p < 0.0001). Conclusions Addition of intermittent bolus-dose vitamin D supplementation to a daily low-dose regimen improved vitamin D status in older adults and their carers, but it did not influence risk of ARI, and was less effective at preventing URI.

Factors Associated With Efficacy of Percutaneous Tibial Nerve Stimulation for Fecal Incontinence, Based on Post-Hoc Analysis of Data From a Randomized Trial

BACKGROUND & AIMS: A recent randomized, multi‐center, phase 3 trial, performed in the United Kingdom (Control of Fecal Incontinence using Distal Neuromodulation Trial), demonstrated no significant clinical benefit of percutaneous tibial nerve stimulation (PTNS) compared to sham stimulation in patients with fecal incontinence (FI). However, this study did not analyze predictors of response. We used data from this trial to identify factors that predict the efficacy of PTNS in adults with FI. METHODS: The study population comprised 205 patients from the CONtrol of Fecal Incontinence using Distal NeuromodulaTion Trial. The primary outcome was a binary indicator of success (≥50% reduction in weekly FI episodes after 12 weeks of treatment) or failure, as per the original trial characteristics including baseline FI symptom type, defecatory urgency, and co‐existent symptoms of baseline liquid stool consistency and obstructive defecation (OD) were defined a priori. Univariable and multivariable analyses were performed to explore these factors as predictors of response to PTNS and sham. RESULTS: In both univariable and multivariable analysis, the presence of OD symptoms negatively predicted outcome in patients who received PTNS (OR, 0.38; 95% CI, 0.16–0.91; P = .029), and positively predicted sham response (OR, 3.45; 95% CI, 1.31–9.21; P = .012). No other tested variable affected outcome. Re‐analysis of the primary outcome excluding patients with OD symptoms (n = 112) resulted in a significant clinical effect of PTNS compared to sham (48.9% vs 18.2% response, P = .002; multivariable OR, 4.71; 95% CI, 1.71–12.93; P = .003). CONCLUSIONS: Concomitant OD symptoms negatively affected the clinical outcome of PTNS vs sham in a major randomized controlled trial. Future appropriately designed studies could further explore this observation with potential for future stratified patient selection.

Surgery for constipation: systematic review and clinical guidance: Paper 1: Introduction & Methods.

This manuscript provides the introduction and detailed methodology used in subsequent reviews to assess the outcomes of surgical interventions with the primary intent of treating chronic constipation in adults and to develop recommendations for practice.

Surgery for constipation: systematic review and practice recommendations: Graded practice and future research recommendations.

This manuscript forms the final of seven that address the surgical management of chronic constipation (CC) in adults. The content coalesces results from the five systematic reviews that precede it and of the European Consensus process to derive graded practice recommendations (GPR).

The CONFIDeNT trial – Authors' reply

1 Knowles CH, Horrocks EJ, Bremner SA, et al. Percutaneous tibial nerve stimulation versus sham electrical stimulation for the treatment of faecal incontinence in adults (CONFIDeNT): a double-blind, multicentre, pragmatic, parallel-group, randomised controlled trial. Lancet 2015; 386: 1640–48. 2 Chen J, Song GQ, Yin J, Koothan T, Chen JD. Electroacupuncture improves impaired gastric motility and slow waves induced by rectal distension in dogs. Am J Physiol Gastrointest Liver Physiol 2008; 295: G614–20. 3 Yi WM, Chen Q, Liu CH, Hou JY, Chen LD, Wu WK. Acupuncture for preventing complications after radical hysterectomy: a randomized controlled clinical trial. Evid Based Complement Alternat Med 2014; 2014: 802134. 4 Liu Z, Wang W, Wu J, Zhou K, Liu B. Electroacupuncture improves bladder and bowel function in patients with traumatic spinal cord injury: results from a prospective observational study. Evid Based Complement Alternat Med 2013; 2013: 543174. 5 Woodward S, Norton C, Barriball KL. A pilot study of the eff ectiveness of refl exology in treating idiopathic constipation in women. Complement Ther Clin Pract 2010; 16: 41–46. 6 Burgell RE, Lelic D, Carrington EV, et al. Assessment of rectal aff erent neuronal function and brain activity in patients with constipation and rectal hyposensitivity. Neurogastroenterol Motil 2013; 25: 260–67. needle. Although the tibial nerve was not stimulated with this arrangement, inadvertent activation of other ascending somatovisceral neuronal pathways cannot be fully excluded. The importance of this possibility is reported in the scientifi c literature, with many studies on distal electroacupuncture away from the tibial nerve reporting efficacy in modulating the pelvic floor. Furthermore, the efficacy of simple foot refl exology on normalising colonic transit in constipation has been reported previously, suggesting the ease by which somatovisceral refl exes can be activated. All patients in the study were blinded to the intervention and probably neuromodulation naive. Knowles and colleagues might have avoided introducing bias by using an inactive stimulation device (ie, with no needle) as a sham. Furthermore, use of a different needle site altogether for sham stimulation might have been a better approach. We are aware that the lead author has used the median nerve as a comparator in previous mechanism studies. The results also show that mean incontinence episodes per week were reduced significantly from 6·0 to 3·5 in the PTNS group (p=0·021). Urge but not passive incontinence improved, and loperamide use was reduced signifi cantly in the PTNS group. These results seem to have been downplayed. The authors raise an important question in their discussion, asking whether the statistically significant improvements are clinically important. Because this was a National Institute for Health Research funded trial, we are aware that a post-trial analysis was done with patient focus groups. We would be most interested to know the opinions of the patients with respect to the question raised by the authors. From our own experience, patients welcome any improvement in symptoms and those improvements described in the results could in fact be clinically relevant. We agree with the authors that a further assessment of patients with sole urge incontinence is important. We read with great interest the Article by Charles Knowles and colleagues about percutaneous tibial nerve stimulation (PTNS) versus sham electrical stimulation for faecal incontinence. We wish to first commend the study group for completing an excellent study and adding to the evidence about this challenging patient group. The study was timely, well balanced, and clinically relevant, and we thank the authors for their eff orts. The group randomly assigned 227 consecutive patients to receive either 12 sessions of PTNS or sham electrical stimulation. Of the 205 participants who completed the treatment (103 for PTNS and 102 for sham), the results suggest no signifi cant benefi t of PTNS versus sham stimulation for the primary outcome—ie, at least 50% reduction in faecal incontinence episodes per week. The results are disappointing and likely to substantially aff ect present faecal incontinence treatment algorithms. For these reasons the conclusions and method of the trial should be examined more closely. We were surprised to learn that a socalled active placebo was chosen for the trial. Patients in the sham group received 10 Hz of stimulation with a pulse width of 200 μs via a needle electrode placed at 2 mm skin depth at the same site as the active stimulation 1 Knowles CH, Horrocks EJ, Bremner SA, et al. Percutaneous tibial nerve stimulation versus sham electrical stimulation for the treatment of faecal incontinence in adults (CONFIDeNT): a double-blind, multicentre, pragmatic, parallel-group, randomised controlled trial. Lancet 2015; 386: 1640–48. 2 Hotouras A, Murphy J, Allison M, et al. Outcome of percutaneous tibial nerve stimulation (PTNS) for fecal incontinence: a prospective cohort study. Ann Surg 2014; 259: 939–43. 3 Hotouras A, Thaha MA, Boyle DJ, et al. Short-term outcome following percutaneous tibial nerve stimulation for faecal incontinence: a single-centre prospective study. Colorectal Dis 2012; 14: 1101–05. 4 de la Portilla F, Laporte M, Maestre MV, et al. Percutaneous neuromodulation of the posterior tibial nerve for the treatment of faecal incontinence—mid-term results: is retreatment required? Colorectal Dis 2014; 16: 304–10.

Faecal incontinence intervention study (FINS): self-management booklet information with or without nurse support to improve continence in people with inflammatory bowel disease: study protocol for a randomized controlled trial

BackgroundInflammatory bowel disease, comprising Crohn’s disease and ulcerative colitis, is a life-long currently incurable illness. It causes bouts of acute intestinal inflammation, in an unpredictable relapsing-remitting course, with bloody diarrhoea and extreme urgency to access a toilet. Faecal incontinence is a devastating social and hygiene problem, impacting heavily on quality of life and ability to work and socialise. Faecal incontinence affects 2–10 % of adults in the general population. People with inflammatory bowel disease have a high risk of incontinence with up to 74 % affected. No previous study has explored conservative interventions for these patients.MethodsThis randomised controlled trial will recruit 186 participants to answer the research question: does implementation of the UK nationally recommended guidance approach to stepwise management of faecal incontinence improve bowel control and quality of life in people with inflammatory bowel disease? We have worked with people with inflammatory bowel disease to translate this guidance into a condition-specific information booklet on managing incontinence. We will randomise participants to receive the booklet, or the booklet plus up to four 30-minute sessions with an inflammatory bowel disease specialist nurse. To be eligible, patients must be in disease remission and report incontinence. The primary outcome measure at 6 months after randomisation is the St Mark’s incontinence score. Other outcomes include quality of life, MY-MOP (generic tool: participants set two goals for intervention, grading goals at baseline and then re-scoring after intervention) and EQ-5D-5 L to enable calculation of quality-adjusted life years. Analysis will be on an intention-to-treat basis. Qualitative interviews will explore participant and health professionals’ views on the interventions.DiscussionFew high-quality studies of conservative interventions in inflammatory bowel disease, and none for faecal incontinence, have been conducted. We have collaborated with patients to design this study. Blinding to this behavioural intervention is not possible, but our self-report outcome measures with a degree of objectivity. There is genuine equipoise between the booklet only and booklet plus nurse arms, and the study will determine if additional support from a nurse is a crucial element in implementing advice.Trial registrationclinitrials.gov.uk: NCT02355834 (Date of registration: 12 December 2014).Protocol version: 4.0. 08.04.15

OC-007 Double blind randomised controlled trial of percutaneous tibial nerve stimulation for the treatment of faecal incontinence in adults

Introduction Percutaneous Tibial Nerve Stimulation (PTNS) is a relatively new ambulatory therapy for faecal incontinence. Case series data suggest beneficial outcomes in 50–80% patients however the effectiveness of PTNS vs. sham has not been trialled. We aimed to assess the short-term efficacy of PTNS compared to sham electrical stimulation in adults with faecal incontinence. Method In this multicentre, parallel-group, double-blind, randomised controlled trial involving 17 UK specialist centres, patients aged 18 years or over with significant faecal incontinence, who had failed conservative treatments were randomly assigned (1:1) to receive either PTNS or sham electrical stimulation. Randomisation was stratified by sex and then by centre in females. Patients and outcome assessors were masked to allocation for the 14-week duration of the trial when the effect of the intervention on severity of FI and quality of life was assessed using bowel diaries and validated questionnaires. A clinical response to treatment (primary outcome) was defined as a ≥50% reduction in weekly FI episodes. Secondary outcomes included reduction in mean weekly FI episodes, summative symptom scores, disease-specific and generic quality of life measures. ISRCTN registration number: 88559475. Results 227 patients were randomised (from 373 screened) to receive PTNS (n = 115) or sham stimulation (n = 112). 12 patients withdrew; 7 from the PTNS group and 5 from the sham group. Missing data were multiply imputed. 39 patients in the PTNS group (38%) had a 50% or greater reduction in weekly FI episodes compared to 32 in the sham group (31%) (OR 1.28, 95% CI 0.72–2.28, p = 0.396). There was a significantly greater decrease in mean total weekly FI episodes in the PTNS compared to sham group (difference in means –2.3, 95% CI (–4.2 to –0.3), p = 0.02). This reflected a significant reduction in mean weekly urge (–1.5, 95% CI (–2.7 to –0.2), p = 0.02) but not passive episodes (–0.64, 95% CI (–1.67 to 0.40), p = 0.23). No significant difference in St Mark’s Continence Score was observed between groups (difference in means –0.047, 95% CI (–1.033 to 0.939), p = 0.93). No differences in the disease-specific Faecal Incontinence Quality of Life and Gastrointestinal Quality of life tools or the generic SF-36 quality of life tool were observed between the groups. No serious adverse events related to treatment were reported. Conclusion PTNS did not confer significant clinical benefit over sham electrical stimulation in the treatment of adults with faecal incontinence. Funding This project was funded by the NIHR Health Technology Assessment programme. Disclosure of interest None Declared.

Electronic informed consent

Informed consent is a critical step in the recruitment of participants to any clinical trial and is essential to ensure participants are properly informed about the purpose of research, how it will be conducted, what is involved, the risks and benefits and rights to withdraw. The informed consent process is heavily regulated to ensure that the rights and wellbeing of trial participants is protected. In the world of electronic media and smart apps, is there a place in UK clinical trials for utilising electronic informed consent? I will report on the current views of research professionals and explore whether electronic informed consent forms (e-ICF) provide the same level of protection for participants rights and wellbeing. I will address the regulatory aspects to be considered and the impact of e-ICF on data protection and confidentiality, as well as centralised trial monitoring for the clinical trials unit. I will focus on the types of trials where electronic informed consent may be appropriate and when it should be avoided. These are the areas that need to be addressed before electronic informed consent can be widely implemented by a clinical trials unit. In future work I will develop a patient focus group to explore e-ICF with patients and the likely impact on recruitment and retention rates and the role of the researcher in the e-ICF process.