BACKGROUND:At least half of all adult women will experience infective cystitis (urinary tract infection: UTI) at least once in their life and many suffer from repeated episodes. Recurrent urinary tract infection (rUTI) in adult women is usually treated with long-term, low-dose antibiotics and current national and international guidelines recommend this as the 'gold standard' preventative treatment. Although they are reasonably effective, long-term antibiotics can result in bacteria becoming resistant not only to the prescribed antibiotic but to other antimicrobial agents. The problem of antimicrobial resistance is recognised as a global threat and the recent drive for antibiotic stewardship has emphasised the need for careful consideration prior to prescribing antibiotics. This has led clinicians and patients alike to explore potential non-antibiotic options for recurrent UTI prevention.DESIGN /METHODS:This is a multicentre, pragmatic, patient-randomised, non-inferiority trial comparing a non-antibiotic preventative treatment for rUTI in women, methenamine hippurate, against the current standard of daily low-dose antibiotics. Women who require preventative treatment for rUTI are the target population. This group is comprised of those with a diagnosis of rUTI, defined as three episodes in 1 year or two episodes in 6 months, and those with a single severe infection requiring hospitalisation. Participants will be recruited from secondary care urology / urogynaecology departments in the UK following referral with rUTI. Participants will be followed up during a 12-month period of treatment and in the subsequent 6 months following completion of the prophylactic medication. Outcomes will be assessed from patient recorded symptoms, quality of life questionnaires and microbiological examination of urine and perineal swabs. The primary outcome is the incidence of symptomatic antibiotic-treated UTI self-reported by participants during the 12-month period of preventative treatment. Health economic outcomes will also be assessed to define the cost-effectiveness of both treatments. A qualitative study will be conducted in the first 8 months of the trial to explore with participants/non-participants' and recruiting clinicians' views on trial processes and identify potential barriers to recruitment, reasons for participating and non-participation and for dropping out of the study.DISCUSSION:The study was commissioned and funded by the National Institute for Health Research (NIHR) and approved under the Medicines and Healthcare products Regulatory Agency (MHRA) notification scheme as a 'Type A' study.TRIAL REGISTRATION:International Standard Randomised Controlled Trial Number (ISRCTN), registry number: ISRCTN70219762 . Registered on 31 May 2016.

Importance:Corticosteroids improve strength and function in boys with Duchenne muscular dystrophy. However, there is uncertainty regarding the optimum regimen and dosage. Objective:To compare efficacy and adverse effects of the 3 most frequently prescribed corticosteroid regimens in boys with Duchenne muscular dystrophy. Design, Setting, and Participants:Double-blind, parallel-group randomized clinical trial including 196 boys aged 4 to 7 years with Duchenne muscular dystrophy who had not previously been treated with corticosteroids; enrollment occurred between January 30, 2013, and September 17, 2016, at 32 clinic sites in 5 countries. The boys were assessed for 3 years (last participant visit on October 16, 2019). Interventions:Participants were randomized to daily prednisone (0.75 mg/kg) (n = 65), daily deflazacort (0.90 mg/kg) (n = 65), or intermittent prednisone (0.75 mg/kg for 10 days on and then 10 days off) (n = 66). Main Outcomes and Measures:The global primary outcome comprised 3 end points: rise from the floor velocity (in rise/seconds), forced vital capacity (in liters), and participant or parent global satisfaction with treatment measured by the Treatment Satisfaction Questionnaire for Medication (TSQM; score range, 0 to 100), each averaged across all study visits after baseline. Pairwise group comparisons used a Bonferroni-adjusted significance level of .017. Results:Among the 196 boys randomized (mean age, 5.8 years [SD, 1.0 years]), 164 (84%) completed the trial. Both daily prednisone and daily deflazacort were more effective than intermittent prednisone for the primary outcome (P < .001 for daily prednisone vs intermittent prednisone using a global test; P = .017 for daily deflazacort vs intermittent prednisone using a global test) and the daily regimens did not differ significantly (P = .38 for daily prednisone vs daily deflazacort using a global test). The between-group differences were principally attributable to rise from the floor velocity (0.06 rise/s [98.3% CI, 0.03 to 0.08 rise/s] for daily prednisone vs intermittent prednisone [P = .003]; 0.06 rise/s [98.3% CI, 0.03 to 0.09 rise/s] for daily deflazacort vs intermittent prednisone [P = .017]; and -0.004 rise/s [98.3% CI, -0.03 to 0.02 rise/s] for daily prednisone vs daily deflazacort [P = .75]). The pairwise comparisons for forced vital capacity and TSQM global satisfaction subscale score were not statistically significant. The most common adverse events were abnormal behavior (22 [34%] in the daily prednisone group, 25 [38%] in the daily deflazacort group, and 24 [36%] in the intermittent prednisone group), upper respiratory tract infection (24 [37%], 19 [29%], and 24 [36%], respectively), and vomiting (19 [29%], 17 [26%], and 15 [23%]). Conclusions and Relevance:Among patients with Duchenne muscular dystrophy, treatment with daily prednisone or daily deflazacort, compared with intermittent prednisone alternating 10 days on and 10 days off, resulted in significant improvement over 3 years in a composite outcome comprising measures of motor function, pulmonary function, and satisfaction with treatment; there was no significant difference between the 2 daily corticosteroid regimens. The findings support the use of a daily corticosteroid regimen over the intermittent prednisone regimen tested in this study as initial treatment for boys with Duchenne muscular dystrophy. Trial Registration:ClinicalTrials.gov Identifier: NCT01603407.

Background: Urethral stricture affects 0.9% of men. Initial treatment is urethrotomy. Approximately, half of the strictures recur within 4 yr. Options for further treatment are repeat urethrotomy or open urethroplasty. Objective: To compare the effectiveness and cost effectiveness of urethrotomy with open urethroplasty in adult men with recurrent bulbar urethral stricture. Design, setting, and participants: This was an open label, two-arm, patient-randomised controlled trial. UK National Health Service hospitals were recruited and 222 men were randomised to receive urethroplasty or urethrotomy. Intervention: Urethrotomy is a minimally invasive technique whereby the narrowed area is progressively widened by cutting the scar tissue with a steel blade mounted on a urethroscope. Urethroplasty is a more invasive surgery to reconstruct the narrowed area. Outcome measurements and statistical analysis: The primary outcome was the profile over 24 mo of a patient-reported outcome measure, the voiding symptom score. The main clinical outcome was time until reintervention. Results and limitations: The primary analysis included 69 (63%) and 90 (81%) of those allocated to urethroplasty and urethrotomy, respectively. The mean difference between the urethroplasty and urethrotomy groups was -0.36 (95% confidence interval [CI] -1.74 to 1.02). Fifteen men allocated to urethroplasty needed a reintervention compared with 29 allocated to urethrotomy (hazard ratio [95% CI] 0.52 [0.31-0.89]). Conclusions: In men with recurrent bulbar urethral stricture, both urethroplasty and urethrotomy improved voiding symptoms. The benefit lasted longer for urethroplasty. Patient summary: There was uncertainty about the best treatment for men with recurrent bulbar urethral stricture. We randomised men to receive one of the following two treatment options: urethrotomy and urethroplasty. At the end of the study, both treatments resulted in similar and better symptom scores. However, the urethroplasty group had fewer reinterventions. (C) 2020 Published by Elsevier B.V. on behalf of European Association of Urology.

BACKGROUND:Men who suffer recurrence of bulbar urethral stricture have to decide between endoscopic urethrotomy and open urethroplasty to manage their urinary symptoms. Evidence of relative clinical effectiveness and cost-effectiveness is lacking.OBJECTIVES:To assess benefit, harms and cost-effectiveness of open urethroplasty compared with endoscopic urethrotomy as treatment for recurrent urethral stricture in men.DESIGN:Parallel-group, open-label, patient-randomised trial of allocated intervention with 6-monthly follow-ups over 24 months. Target sample size was 210 participants providing outcome data. Participants, clinicians and local research staff could not be blinded to allocation. Central trial staff were blinded when needed.SETTING:UK NHS with recruitment from 38 hospital sites.PARTICIPANTS:A total of 222 men requiring operative treatment for recurrence of bulbar urethral stricture who had received at least one previous intervention for stricture.INTERVENTIONS:A centralised randomisation system using random blocks allocated participants 1 : 1 to open urethroplasty (experimental group) or endoscopic urethrotomy (control group).MAIN OUTCOME MEASURES:The primary clinical outcome was control of urinary symptoms. Cost-effectiveness was assessed by cost per quality-adjusted life-year (QALY) gained over 24 months. The main secondary outcome was the need for reintervention for stricture recurrence.RESULTS:The mean difference in the area under the curve of repeated measurement of voiding symptoms scored from 0 (no symptoms) to 24 (severe symptoms) between the two groups was -0.36 [95% confidence interval (CI) -1.78 to 1.02; p = 0.6]. Mean voiding symptom scores improved between baseline and 24 months after randomisation from 13.4 [standard deviation (SD) 4.5] to 6 (SD 5.5) for urethroplasty group and from 13.2 (SD 4.7) to 6.4 (SD 5.3) for urethrotomy. Reintervention was less frequent and occurred earlier in the urethroplasty group (hazard ratio 0.52, 95% CI 0.31 to 0.89; p = 0.02). There were two postoperative complications requiring reinterventions in the group that received urethroplasty and five, including one death from pulmonary embolism, in the group that received urethrotomy. Over 24 months, urethroplasty cost on average more than urethrotomy (cost difference £2148, 95% CI £689 to £3606) and resulted in a similar number of QALYs (QALY difference -0.01, 95% CI -0.17 to 0.14). Therefore, based on current evidence, urethrotomy is considered to be cost-effective.LIMITATIONS:We were able to include only 69 (63%) of the 109 men allocated to urethroplasty and 90 (80%) of the 113 men allocated to urethrotomy in the primary complete-case intention-to-treat analysis.CONCLUSIONS:The similar magnitude of symptom improvement seen for the two procedures over 24 months of follow-up shows that both provide effective symptom control. The lower likelihood of further intervention favours urethroplasty, but this had a higher cost over the 24 months of follow-up and was unlikely to be considered cost-effective.FUTURE WORK:Formulate methods to incorporate short-term disutility data into cost-effectiveness analysis. Survey pathways of care for men with urethral stricture, including the use of enhanced recovery after urethroplasty. Establish a pragmatic follow-up schedule to allow national audit of outcomes following urethral surgery with linkage to NHS Hospital Episode Statistics.TRIAL REGISTRATION:Current Controlled Trials ISRCTN98009168.FUNDING:This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 61. See the NIHR Journals Library website for further project information.

Background: The visually impaired have a higher risk of falling and are likely to avoid activity. Objectives: To adapt the existing Falls Management Exercise (FaME) programme, which is delivered in the community, for visually impaired older people (VIOP) and to investigate the feasibility of conducting a definitive randomised controlled trial of this adapted intervention. Design: Phase I – consultation with stakeholders to adapt the existing programme. Two focus groups were conducted, each with 10 VIOP across the study sites. Phase II – two-centre randomised pilot trial and economic evaluation of the adapted programme for VIOP versus usual care. Phases III and IV – qualitative interviews with VIOP and Postural Stability Instructors regarding their views and experiences of the research process, undertaking the intervention and its acceptability. Intervention: This was adapted from the group-based FaME programme. A 1-hour exercise programme ran weekly over 12 weeks at the study sites (Newcastle upon Tyne and Glasgow) and was delivered by third-sector organisations. Participants were advised to also exercise at home for 2 hours per week. Those randomised to the usual activities group received no intervention. Outcome measures: These were completed at baseline, week 12 and week 24. The primary potential outcome measure used was the Short Form Falls Efficacy Scale – International. Secondary outcome assessment measures were activity avoidance, current activity, balance/falls risk, physical activity, loneliness, anxiety and depression, work and social adjustment, quality of life and economic costs. Participants’ compliance was assessed by reviewing attendance records and self-reported compliance with the home exercises. Instructors’ compliance with the course content (fidelity) was assessed by a researcher attending a sample of exercise sessions. Adverse events were collected in a weekly telephone call for all participants in both the intervention and control arm. Findings: An adapted exercise programme was devised with stakeholders. In the pilot trial, 82 participants drawn from community-living VIOP were screened, 68 met the inclusion criteria and 64 were randomised, with 33 allocated to the intervention and 31 to the usual activities arm. A total of 94% of participants provided data at week 12 and 92% at week 24. Adherence to the study was high. The intervention was found to be both safe and acceptable to participants, with 76% attending nine or more classes. Median time for home exercise was 50 minutes per week. There was little or no evidence that fear of falling, exercise, attitudinal or quality-of-life outcomes differed between trial arms at follow-up. Thematic analysis of the interviews with VIOP participants identified facilitators of and barriers to exercise, including perceived relevance to health, well-being and lifestyle, social interaction, self-perception and practical assistance. Instructors identified issues regarding level of challenge and assistance from a second person. Limitations: The small sample size and low falls risk of the study sample are study limitations. Conclusion: Although adaptation, recruitment and delivery were successful, the findings (particularly from qualitative research with instructors and participants) indicated that VIOP with low to moderate falls risk could be integrated into mainstream programmes with some adaptations. A future definitive trial should consider graduated exercises appropriate to ability and falls risk within mainstream provision. Other outcome measures may additionally be considered. Trial registration: Current Controlled Trials ISRCTN16949845. Funding: This project was funded by the NIHR Public Health Research programme and will be published in full in Public Health Research; Vol. 7, No. 4. See the NIHR Journals Library website for further project information.

Background: Primary biliary cirrhosis (PBC) is an autoimmune liver disease, and 50% of patients with this disease experience fatigue. This is a debilitating symptom affecting quality of life and resulting in social isolation, which is highlighted by patients as a research priority. PBC is characterised immunologically by the presence of high-titre autoantibodies that are directed at the pyruvate dehydrogenase complex (PDC) and are highly effective at blocking its energy generation function. We hypothesised that if anti-PDC antibodies were a driver of fatigue through bioenergetic dysfunction, then the B-cell-targeting biological agent rituximab (MabThera®, Roche Products Ltd, Welwyn Garden City, UK) might be a therapeutic option. Objective: To assess whether or not rituximab safely improved moderate or severe fatigue in PBC patients. Design: A Phase II, double-blind, randomised controlled trial comparing rituximab with placebo in fatigued PBC patients. Randomisation was conducted using a web-based system. Participants received two infusions on days 1 and 15 and were followed up at 3, 6, 9 and 12 months. Setting: A single-centre UK study in Newcastle upon Tyne Hospitals NHS Foundation Trust. Participants: Seventy-one participants aged ≥ 18 years with PBC and moderate or severe fatigue (score of > 33 on the PBC-40 fatigue domain) were screened. The PBC-40 questionnaire is a fully validated disease-specific health-related quality-of-life measure for use in patients with PBC. Fatigue, with a maximum score of 55, is one of its six domains. Fifty-seven participants were randomised to the trial, 55 of whom reached the primary end-point assessment. Intervention: Participants were randomised in a 1 : 1 ratio to receive either rituximab (1000 mg) or a saline intravenous infusion (placebo) on days 1 and 15. The infusions were delivered in a double-blind manner using the same protocol. Main outcome measures: The primary outcome measure was the PBC-40 fatigue domain at 3 months, assessed on an intention-to-treat basis. Secondary outcome measures included markers of bioenergetics function (anaerobic threshold and post-exercise muscle pH assessed using magnetic resonance imaging) and physical activity levels. Impact on biochemical markers of liver disease severity was assessed as an experimental outcome. Results: Rituximab therapy was safe, with no serious adverse events linked to the drug. There was no statistically significant difference in fatigue score at 3 months between the rituximab and placebo arms [adjusted mean difference –0.9, 95% confidence interval (CI) –4.6 to 3.1]. However, improvement in fatigue was observed in both arms {mean score decreasing from 41.2 [standard deviation (SD) 5.5] to 36.2 (SD 8.4) in the rituximab arm and from 43.0 (SD 5.9) to 38.1 (SD 8.7) in the placebo arm}. There was little difference in any of the secondary outcomes between arms. However, anaerobic threshold improved significantly in the rituximab arm (adjusted mean difference at 3 months 1.41, 95% CI 0.03 to 2.80). No change in muscle bioenergetics characteristics was seen. A suggestive improvement in liver biochemistry was observed. Limitations: Recruitment was lower than the original target, leading to a reduction in study power. A clinically significant placebo effect on PBC-40 fatigue scores was seen. Conclusions: Rituximab is ineffective for the treatment of fatigue in unselected PBC patients despite metabolic modulation through improvement of anaerobic threshold. Future work: Results from the trial demonstrate that metabolic effect of rituximab is not translated into clinical benefit. This will help to guide us to design future trials and when looking at completely different targets. Trial registration: Current Controlled Trials ISRCTN03978701, ClinicalTrials.gov identifier NCT02376335 and EudraCT number 2012-000145-12. Funding: This project was funded by the National Institute for Health Research (NIHR) Efficacy and Mechanism Evaluation programme and will be published in full in Efficacy and Mechanism Evaluation; Vol. 5, No. 2. See the NIHR Journals Library website for further project information. Additional funding was received from the Medical Research Council and a Department of Health and Social Care subvention.

Background Hand eczema is a common inflammatory dermatosis that causes significant patient morbidity. Previous studies comparing psoralen-ultraviolet A (PUVA) with narrowband ultraviolet B (NB-UVB) have been small, nonrandomized and retrospective. Objectives To conduct an observer-blinded randomized controlled pilot study using validated scoring criteria to compare immersion PUVA with NB-UVB for the treatment of chronic hand eczema unresponsive to topical steroids. Methods Sixty patients with hand eczema unresponsive to clobetasol propionate 0.05% were randomized to receive either immersion PUVA or NB-UVB twice weekly for 12 weeks with assessments at intervals of 4 weeks. The primary Out-come measure was the proportion of patients achieving 'clear' or 'almost clear' Physician's Global Assessment (PGA) response at 12 weeks. Secondary outcome measures included assessment of the modified Total Lesion and Symptom Score (mTLSS) and the Dermatology Life Quality index (DLQI). Results In both treatment arms, 23 patients completed the 12-week assessment for the primary outcome measure. In the PUVA group, five patients achieved 'clear' and eight 'almost clear' [intention-to-treat (ITT) response rate 43%]. In the NB-UVB group, two achieved 'clear' and five 'almost clear' (ITT response rate 23%). For the secondary outcomes, median mTLSS scores were similar between groups at baseline (PUVA 9.5, NB-UVB 9) and at 12 weeks (PUVA 3, NB-UVB 4). Changes in DLQI were similar, with improvements in both groups. Conclusions In this randomized pilot trial recruitment was challenging. After randomization, there were acceptable levels of compliance and safety in each treatment schedule, but lower levels of retention. Using validated scoring systems - PGA, mTLSS and DLQI - as measures of treatment response, the trial demonstrated that both PUVA and NB-UVB reduced the severity of chronic palmar hand eczema.

手部湿疹是最常见的皮肤病之一,某些研究估计,多达10%的欧洲人口在某个阶段患有一定程度的手部湿疹。手部湿疹病因多样,一些人具有基因倾向,另一些人患上手部湿疹是因为所从事的工作,通常是因为在医疗或酒店行业频繁洗手。手部湿疹的初步治疗是避免明显的触发因素以及使用大量保湿霜。如果问题继续,要由医生开具类固醇乳膏。这些措施通常足以治愈湿疹,但是如果湿疹继续,则医生会提供基于紫外线(UV)的光线治疗或药片治疗。本研究调查了两种不同形式的UV光线治疗,用于治疗湿疹。PUVA包括先在光敏性药物水溶液中浸泡双手再接受UVA光线5‐15分钟,而NBUVB则是在UVB光线中暴露1‐2分钟。PUVA是一种传统治疗,已经应用30年之久。该疗法非常耗时。有些医生担心过量使用PUVA可能增加皮肤癌的风险,因此无限重复的治疗通常不会被采纳。本研究邀请手部湿疹使用类固醇乳膏未得到改善的患者,接受PUVA或UVB治疗。研究人员分别在治疗之前、期间和之后对其手部湿疹的严重程度进行了评分。由于难以招募足够的患者,很难说出哪种治疗更好。不过,该研究确实表明,两种治疗都能改善湿疹严重程度。NBUVB治疗存在更多副作用,主要是轻微的皮肤发红。本研究提供了有关的新信息。我们现在知道,NBUVB是一种安全且可行的手部湿疹治疗方法。它确实会改善手部湿疹严重程度。与PUVA相比,它耗费时间更短,但会产生更多副作用。我们利用官方评分系统衡量了患者接受两种治疗后的湿疹改善,这意味着我们现在能够设计更大规模的临床试验,来确定哪种治疗更加有效。

Trials in rare diseases have many challenges, among which are the need to set up multiple sites in different countries to achieve recruitment targets and the divergent landscape of clinical trial regulations in those countries. Over the past years, there have been initiatives to facilitate the process of international study set-up, but the fruits of these deliberations require time to be operationally in place. FOR-DMD (Finding the Optimum Steroid Regimen for Duchenne Muscular Dystrophy) is an academic-led clinical trial which aims to find the optimum steroid regimen for Duchenne muscular dystrophy, funded by the National Institutes of Health (NIH) for 5 years (July 2010 to June 2015), anticipating that all sites (40 across the USA, Canada, the UK, Germany and Italy) would be open to recruitment from July 2011. However, study start-up was significantly delayed and recruitment did not start until January 2013.

Hand eczema is one of the most common skin diseases with some studies estimating that up to 10% of the European population has some degree of hand eczema at any one time. There are various causes with some people having a genetic tendency and others developing hand eczema due to their jobs, often a result of hand washing in healthcare or hospitality sectors. The initial treatment of hand eczema is to avoid obvious triggers and use plenty of moisturising creams. If problems continue steroid creams are prescribed. These measures are often enough but if the eczema continues patients are then offered either ultraviolet (UV) light based treatments or tablets. This research study investigated two different forms of UV light treatment which are used to treat eczema. PUVA involves soaking the hands in a water-based solution of a photosensitising drug before receiving UVA light for 5-15 minutes whereas NBUVB involves a 1-2 minute exposure to UVB light. PUVA is the traditional treatment and has been used for 30 years. It is time consuming. There are some concerns that excessive PUVA use could increase the risk of skin cancers and indefinite repeated treatment is not used. The research study invited patients with hand eczema not improving with steroid creams to receive either PUVA or UVB treatment. The severity of their eczema was scored before, during and after treatment. Due to difficulties in recruiting enough patients it was not possible to say which treatment was better. However, the study did show that both treatments improved the eczema severity. There were more side effects with the NBUVB treatment mainly due to mild episodes of skin redness. This research has provided new information. We now know that NBUVB is a safe and acceptable treatment for hand eczema. It does lead to improvement in hand eczema severity. It takes less time but does produce more side effects than PUVA. We have measured the improvement in patients’ eczema with both treatments using official scoring systems which means we are now in a position to design a larger clinical trial to determine which treatment is more effective.

IntroductionAlthough cardiologists were ‘late-comers’ to the multidisciplinary team—contributing to the complex care of patients with Duchenne muscular dystrophy (DMD), they now recognise the importance of systematic cardiac surveillance and timely therapy to prolonged survival in patients with DMD. Empirical deployment of cardioactive medications has already improved outcomes, but the evidence base for clinical decision making is weak. Fundamental questions remain as to whether prophylactic therapy is justified and convincingly superior to prompt deployment of the same therapies once left ventricular (LV) dysfunction is detected. Even if it were, at what age should therapy be introduced and with what specific drugs?Methods and analysisWe are conducting a multicentre, parallel group, randomised, placebo-controlled study of combination therapy with an ACE inhibitor (perindopril) and a beta-blocker (bisoprolol) in boys with DMD aged 5–13 years, with normal LV function by echocardiographic criteria at the time of recruitment. Boys are being followed-up for a minimum of 3 years and a maximum of 5 years and undergo repeat assessments of LV function, heart rate and ECG, forced expiratory volume in the 1 s and forced vital capacity, adverse event reporting and quality of life at 6 monthly intervals.The primary outcome is change in LV function between active and placebo-treated participants over the course of the study.Ethics and disseminationThe study was approved by ‘NRES Committee East Midlands – Derby’. The results will be disseminated through manuscript publications, an international workshop and presentations to scientific meetings and parent forums.Translational aspectsThe study seeks to establish the evidence for prophylactic heart therapies for children with DMD, define the optimum age for their introduction and identify any safety concerns.Article summaryThe protocol describes the design of an ongoing multicentre, double-blind, randomised placebo-controlled study to establish the evidence for the use of prophylactic heart therapies in children with DMD, define the optimum age for their introduction and identify any safety concerns.Trial registration numbersEudraCT2007-005932-10 andISRCTN50395346; Pre-results.

BackgroundPeople carrying out clean intermittent self-catheterisation (CISC) to empty their bladder often suffer repeated urinary tract infections (UTIs). Continuous once-daily, low-dose antibiotic treatment (antibiotic prophylaxis) is commonly advised but knowledge of its effectiveness is lacking.ObjectiveTo assess the benefit, harms and cost-effectiveness of antibiotic prophylaxis to prevent UTIs in people who perform CISC.DesignParallel-group, open-label, patient-randomised 12-month trial of allocated intervention with 3-monthly follow-up. Outcome assessors were blind to allocation.SettingUK NHS, with recruitment of patients from 51 sites.ParticipantsFour hundred and four adults performing CISC and predicted to continue for ≥ 12 months who had suffered at least two UTIs in the previous year or had been hospitalised for a UTI in the previous year.InterventionsA central randomisation system using random block allocation set by an independent statistician allocated participants to the experimental group [once-daily oral antibiotic prophylaxis using either 50 mg of nitrofurantoin, 100 mg of trimethoprim (Kent Pharmaceuticals, Ashford, UK) or 250 mg of cefalexin (Sandoz Ltd, Holzkirchen, Germany);n = 203] or the control group of no prophylaxis (n = 201), both for 12 months.Main outcome measuresThe primary clinical outcome was relative frequency of symptomatic, antibiotic-treated UTI. Cost-effectiveness was assessed by cost per UTI avoided. The secondary measures were microbiologically proven UTI, antimicrobial resistance, health status and participants’ attitudes to antibiotic use.ResultsThe frequency of symptomatic antibiotic-treated UTI was reduced by 48% using prophylaxis [incidence rate ratio (IRR) 0.52, 95% confidence interval (CI) 0.44 to 0.61;n = 361]. Reduction in microbiologically proven UTI was similar (IRR 0.49, 95% CI 0.39 to 0.60;n = 361). Absolute reduction in UTI episodes over 12 months was from a median (interquartile range) of 2 (1–4) in the no-prophylaxis group (n = 180) to 1 (0–2) in the prophylaxis group (n = 181). The results were unchanged by adjustment for days at risk of UTI and the presence of factors giving higher risk of UTI. Development of antimicrobial resistance was seen more frequently in pathogens isolated from urine andEscherichia colifrom perianal swabs in participants allocated to antibiotic prophylaxis. The use of prophylaxis incurred an extra cost of £99 to prevent one UTI (not including costs related to increased antimicrobial resistance). The emotional and practical burden of CISC and UTI influenced well-being, but health status measured over 12 months was similar between groups and did not deteriorate significantly during UTI. Participants were generally unconcerned about using antibiotics, including the possible development of antimicrobial resistance.LimitationsLack of blinding may have led participants in each group to use different thresholds to trigger reporting and treatment-seeking for UTI.ConclusionsThe results of this large randomised trial, conducted in accordance with best practice, demonstrate clear benefit for antibiotic prophylaxis in terms of reducing the frequency of UTI for people carrying out CISC. Antibiotic prophylaxis use appears safe for individuals over 12 months, but the emergence of resistant urinary pathogens may prejudice longer-term management of recurrent UTI and is a public health concern. Future work includes longer-term studies of antimicrobial resistance and studies of non-antibiotic preventative strategies.Trial registrationCurrent Controlled Trials ISRCTN67145101 and EudraCT 2013-002556-32.FundingThis project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in full inHealth Technology AssessmentVol. 22, No. 24. See the NIHR Journals Library website for further project information.

Summary Background Repeated symptomatic urinary tract infections (UTIs) affect 25% of people who use clean intermittent self-catheterisation (CISC) to empty their bladder. We aimed to determine the benefits, harms, and cost-effectiveness of continuous low-dose antibiotic prophylaxis for prevention of recurrent UTIs in adult users of CISC. Methods In this randomised, open-label, superiority trial, we enrolled participants from 51 UK National Health Service organisations. These participants were community-dwelling (as opposed to hospital inpatient) users of CISC with recurrent UTIs. We randomly allocated participants (1:1) to receive either antibiotic prophylaxis once daily (prophylaxis group) or no prophylaxis (control group) for 12 months by use of an internet-based system with permuted blocks of variable length. Trial and laboratory staff who assessed outcomes were masked to allocation but participants were aware of their treatment group. The primary outcome was the incidence of symptomatic, antibiotic-treated UTIs over 12 months. Participants who completed at least 6 months of follow-up were assumed to provide a reliable estimate of UTI incidence and were included in the analysis of the primary outcome. Change in antimicrobial resistance of urinary and faecal bacteria was monitored as a secondary outcome. The AnTIC trial is registered at ISRCTN, number 67145101; and EudraCT, number 2013-002556-32.