Habit training versus habit training with direct visual biofeedback in adults with chronic constipation: A randomized controlled trial.

AIM: The aim was to determine whether specialist-led habit training using Habit Training with Biofeedback (HTBF) is more effective than specialist-led habit training alone (HT) for chronic constipation and whether outcomes of interventions are improved by stratification to HTBF or HT based on diagnosis (functional defaecation disorder vs. no functional defaecation disorder) by radio-physiological investigations (INVEST). METHOD: This was a parallel three-arm randomized single-blinded controlled trial, permitting two randomized comparisons: HTBF versus HT alone; INVEST- versus no-INVEST-guided intervention. The inclusion criteria were age 18-70 years; attending specialist hospitals in England; self-reported constipation for >6 months; refractory to basic treatment. The main exclusions were secondary constipation and previous experience of the trial interventions. The primary outcome was the mean change in Patient Assessment of Constipation Quality of Life score at 6 months on intention to treat. The secondary outcomes were validated disease-specific and psychological questionnaires and cost-effectiveness (based on EQ-5D-5L). RESULTS: In all, 182 patients were randomized 3:3:2 (target 384): HT n = 68; HTBF n = 68; INVEST-guided treatment n = 46. All interventions had similar reductions (improvement) in the primary outcome at 6 months (approximately -0.8 points of a 4-point scale) with no statistically significant difference between HT and HTBF (-0.03 points; 95% CI -0.33 to 0.27; P = 0.85) or INVEST versus no-INVEST (0.22; -0.11 to 0.55; P = 0.19). Secondary outcomes showed a benefit for all interventions with no evidence of greater cost-effectiveness of HTBF or INVEST compared with HT. CONCLUSION: The results of the study at 6 months were inconclusive. However, with the caveat of under-recruitment and further attrition at 6 months, a simple, cheaper approach to intervention may be as clinically effective and more cost-effective than more complex and invasive approaches.

Efficacy and mechanism of sub-sensory sacral (optimised) neuromodulation in adults with faecal incontinence: study protocol for a randomised controlled trial.

BACKGROUND: Faecal incontinence (FI) is a substantial health problem with a prevalence of approximately 8% in community-dwelling populations. Sacral neuromodulation (SNM) is considered the first-line surgical treatment option in adults with FI in whom conservative therapies have failed. The clinical efficacy of SNM has never been rigorously determined in a trial setting and the underlying mechanism of action remains unclear. METHODS/DESIGN: The design encompasses a multicentre, randomised, double-blind crossover trial and cohort follow-up study. Ninety participants will be randomised to one of two groups (SNM/SHAM or SHAM/SNM) in an allocation ratio of 1:1. The main inclusion criteria will be adults aged 18-75 years meeting Rome III and ICI definitions of FI, who have failed non-surgical treatments to the UK standard, who have a minimum of eight FI episodes in a 4-week screening period, and who are clinically suitable for SNM. The primary objective is to estimate the clinical efficacy of sub-sensory SNM vs. SHAM at 32 weeks based on the primary outcome of frequency of FI episodes using a 4-week paper diary, using mixed Poisson regression analysis on the intention-to-treat principle. The study is powered (0.9) to detect a 30% reduction in frequency of FI episodes between sub-sensory SNM and SHAM stimulation over a 32-week crossover period. Secondary objectives include: measurement of established and new clinical outcomes after 1 year of therapy using new (2017 published) optimised therapy (with standardised SNM-lead placement); validation of new electronic outcome measures (events) and a device to record them, and identification of potential biological effects of SNM on underlying anorectal afferent neuronal pathophysiology (hypothesis: SNM leads to increased frequency of perceived transient anal sphincter relaxations; improved conscious sensation of defaecatory urge and cortical/subcortical changes in afferent responses to anorectal electrical stimulation (main techniques: high-resolution anorectal manometry and magnetoencephalography). DISCUSSION: This trial will determine clinical effect size for sub-sensory chronic electrical stimulation of the sacral innervation. It will provide experimental evidence of modifiable afferent neurophysiology that may aid future patient selection as well as a basic understanding of the pathophysiology of FI. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number: ISRCTN98760715 . Registered on 15 September 2017.

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.

Habit training versus habit training with direct visual biofeedback in adults with chronic constipation: study protocol for a randomised controlled trial.

BACKGROUND: Constipation affects up to 20% of adults. Chronic constipation (CC) affects 1-2% of adults. Patient dissatisfaction is high; nearly 80% feel that laxative therapy is unsatisfactory and symptoms have significant impact on quality of life. There is uncertainty about the value of specialist investigations and whether equipment-intensive therapies using biofeedback confer additional benefit when compared with specialist conservative advice. METHODS/DESIGN: A three-arm, parallel-group, multicentre randomised controlled trial. OBJECTIVES: to determine whether standardised specialist-led habit training plus pelvic floor retraining using computerised biofeedback is more clinically effective than standardised specialist-led habit training alone; to determine whether outcomes are improved by stratification based on prior investigation of anorectal and colonic pathophysiology. Primary outcome measure is response to treatment, defined as a 0.4-point (10% of scale) or greater reduction in Patient Assessment of Constipation-Quality of Life (PAC-QOL) score 6 months after the end of treatment. Other outcomes up to 12 months include symptoms, quality of life, health economics, psychological health and qualitative experience. HYPOTHESES: (1) habit training (HT) with computer-assisted direct visual biofeedback (HTBF) results in an average reduction in PAC-QOL score of 0.4 points at 6 months compared to HT alone in unselected adults with CC, (2) stratification to either HT or HTBF informed by pathophysiological investigation (INVEST) results in an average 0.4-point reduction in PAC-QOL score at 6 months compared with treatment not directed by investigations (No-INVEST). Inclusion: chronic constipation in adults (aged 18-70 years) defined by self-reported symptom duration of more than 6 months; failure of previous laxatives or prokinetics and diet and lifestyle modifications. Consenting participants (n = 394) will be randomised to one of three arms in an allocation ratio of 3:3:2: [1] habit training, [2] habit training and biofeedback or [3] investigation-led allocation to one of these arms. Analysis will be on an intention-to-treat basis. DISCUSSION: This trial has the potential to answer some of the major outstanding questions in the management of chronic constipation, including whether costly invasive tests are warranted and whether computer-assisted direct visual biofeedback confers additional benefit to well-managed specialist advice alone. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number: ISRCTN11791740. Registered on 16 July 2015.

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 manufacturer's 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 Mark's 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.

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.

BACKGROUND: Percutaneous tibial nerve stimulation (PTNS) is a new ambulatory therapy for faecal incontinence. Data from case series suggest it has beneficial outcomes in 50-80% patients; however its effectiveness against sham electrical stimulation has not been investigated. We therefore aimed to assess the short-term efficacy of PTNS against sham electrical stimulation in adults with faecal incontinence. METHODS: We did a double-blind, multicentre, pragmatic, parallel-group, randomised controlled trial (CONtrol of Faecal Incontinence using Distal NeuromodulaTion [CONFIDeNT]) in 17 specialist hospital units in the UK that had the skills to manage patients with faecal incontinence. Eligible participants aged 18 years or older with substantial faecal incontinence for whom conservative treatments (such as dietary changes and pelvic floor exercises) had not worked, were randomly assigned (1:1) to receive either PTNS (via the Urgent PC neuromodulation system) or sham stimulation (via a transcutaneous electrical nerve stimulation machine to the lateral forefoot) once per week for 12 weeks. Randomisation was done with permuted block sizes of two, four, and six, and was stratified by sex and then by centre for women. Patients and outcome assessors were both masked to treatment allocation for the 14-week duration of the trial (but investigators giving the treatment were not masked). The primary outcome was a clinical response to treatment, which we defined as a 50% or greater reduction in episodes of faecal incontinence per week. We assessed this outcome after 12 treatment sessions, using data from patients' bowel diaries. Analysis was by intention to treat, and missing data were multiply imputed. This trial is registered with the ISRCTN registry, number 88559475, and is closed to new participants. FINDINGS: Between Jan 23, 2012, and Oct 31, 2013, we randomly assigned 227 eligible patients (of 373 screened) to receive either PTNS (n=115) or sham stimulation (n=112). 12 patients withdrew from the trial: seven from the PTNS group and five from the sham group (mainly because they could not commit to receiving treatment every week). Two patients (one in each group) withdrew because of an adverse event that was unrelated to treatment (exacerbation of fibromyalgia and rectal bleeding). 39 (38%) of 103 patients with full data from bowel diaries in the PTNS group had a 50% or greater reduction in the number of episodes of faecal incontinence per week compared with 32 (31%) of 102 patients in the sham group (adjusted odds ratio 1·28, 95% CI 0·72-2·28; p=0·396). No serious adverse events related to treatment were reported in the trial. Seven mild, related adverse events were reported in each treatment group, mainly pain at the needle site (four in PTNS, three in sham). INTERPRETATION: PTNS given for 12 weeks did not confer significant clinical benefit over sham electrical stimulation in the treatment of adults with faecal incontinence. Further studies are warranted to determine its efficacy in the long term, and in patient subgroups (ie, those with urgency). FUNDING: National Institute for Health Research.

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.