John Norrie

Types of urethral catheter for reducing symptomatic urinary tract infections in hospitalised adults requiring short-term catheterisation: multicentre randomised controlled trial and economic evaluation of antimicrobial- and antiseptic-impregnated urethral catheters (the CATHETER trial)

BACKGROUNDnCatheter-associated urinary tract infection (CAUTI) is a major preventable cause of harm for patients in hospital and incurs significant costs for health-care providers such as the UK NHS. Many preventative strategies and measures have been introduced to minimise CAUTI risk, including the use of antimicrobial catheters. However, there is considerable uncertainty regarding their usefulness in terms of reducing symptomatic CAUTI, and whether or not they are cost-effective.nnnOBJECTIVESnDo antimicrobial catheters reduce the rate of symptomatic urinary tract infection (UTI) during short-term hospital use and is their use cost-effective for the UK NHS?nnnDESIGNnA pragmatic multicentre UK randomised controlled trial comparing three catheters as they would be used in the UK NHS: antimicrobial-impregnated (nitrofurazone) and antiseptic-coated (silver alloy) catheters with the standard polytetrafluoroethylene (PTFE)-coated catheters. Economic evaluation used a decision model populated with data from the trial. Sensitivity analysis was used to explore uncertainty.nnnSETTINGnRelevant clinical departments in 24 NHS hospitals throughout the UK.nnnPARTICIPANTSnAdults requiring temporary urethral catheterisation for a period of between 1 and 14 days as part of their care, predominantly as a result of elective surgery.nnnINTERVENTIONSnEligible participants were randomised 1 : 1 : 1 to one of three types of urethral catheter in order to make the following pragmatic comparisons: nitrofurazone-impregnated silicone catheter compared with standard PTFE-coated latex catheter; and silver alloy-coated hydrogel latex catheter compared with standard PTFE-coated latex catheter.nnnMAIN OUTCOME MEASURESnThe primary outcome for clinical effectiveness was the incidence of UTI at any time up to 6 weeks post randomisation. This was defined as any symptom reported during catheterisation, up to 3 days or 1 or 2 weeks post catheter removal or 6 weeks post randomisation combined with a prescription of antibiotics, at any of these times, for presumed symptomatic UTI. The primary economic outcome was incremental cost per quality-adjusted life-year (QALY). Health-care costs were estimated from NHS sources with QALYs calculated from participant completion of the European Quality of Life-5 Dimensions (EQ-5D).nnnRESULTSnOutcome analyses encompassed 6394 (90%) of 7102 participants randomised. The rate of symptomatic UTI within 6 weeks of randomisation was 10.6% in the nitrofurazone group (n = 2153; -2.1% absolute risk difference), 12.5% in the silver alloy group (n = 2097; -0.1% absolute risk difference) and 12.6% in the PTFE group (n = 2144). The effect size {odds ratio (OR) [97.5% confidence interval (CI)]} was 0.82 (97.5% CI 0.66 to 1.01) for nitrofurazone (p = 0.037) and 0.99 (97.5% CI 0.81 to 1.22) for silver alloy (p = 0.92) catheters. The nitrofurazone catheters were more likely to cause discomfort during use and on removal. The primary economic analysis suggested that nitrofurazone-impregnated catheters would be, on average, the least costly (> £7 less than PTFE) and most effective option at current NHS prices. There was a 73% chance that nitrofurazone would be cost saving and an 84% chance that the incremental cost per QALY would be < £30,000. At the trial price (£6.46), silver alloy catheters were very unlikely to be cost-effective. These results were unchanged in sensitivity analyses, although when the length of stay cost was excluded the incremental cost per QALY for nitrofurazone against PTFE was £28,602.nnnCONCLUSIONSnThe trial estimate of clinical effectiveness for nitrofurazone-impregnated catheters was less than the pre-specified minimum absolute risk difference that we considered important (-3.3%), and the surrounding CI included zero, indicating that any reduction in catheter-associated UTI was uncertain. Economic analysis, although associated with uncertainty, suggested that nitrofurazone-impregnated catheters may be cost-effective for the NHS. The trial ruled out the possibility that silver alloy-coated catheters might reach the pre-set degree of clinical effectiveness and that their use was unlikely to be cost-effective. These findings should be considered by patients, clinicians and health-care policy-makers to determine whether or not a change in practice is worthwhile. Future research should be aimed at determining the minimum clinically important difference in terms of CAUTI prevention in comparative trials, and to identify reliable methods which can detect the impact of the intervention on quality of life and other drivers of cost, when the intervention is a subsidiary part of overall treatment plans.

Alcohol and disadvantaged men: A feasibility trial of an intervention delivered by mobile phone

Abstract Introduction and Aims Disadvantaged men suffer substantial harm from heavy drinking. This feasibility study developed and evaluated the methods for a trial of a brief intervention delivered by text messages to disadvantaged men. It aimed to test the methods for recruitment and retention, to monitor engagement with the intervention and assess the overall acceptability of study methods. Design and Methods Disadvantaged men aged 25–44u2009years who had ≥2 episodes of binge drinking (≥8 units in one session) in the preceding month were recruited. Two recruitment strategies were assessed: recruitment from general practice registers and by a community outreach strategy. Theoretically and empirically based text messages were tailored to the target group. Results The study recruited 67 disadvantaged men at high risk of alcohol‐related harm, exceeding the target of 60. Evaluation showed that 95% of text messages were delivered, and the men engaged enthusiastically with the intervention. Retention at follow up was 96%. Outcomes were successfully measured on all men followed up. This provided data for the sample size calculation for the full trial. Post‐study evaluation showed high levels of satisfaction with the study. Discussion and Conclusions This study has shown that disadvantaged men can be recruited and follow‐up data obtained in an alcohol intervention study. The study methods were acceptable to the participants. The men recruited were at high risk of alcohol‐related harms. It also clarified ways in which the recruitment strategy, the baseline questionnaire and the intervention could be improved. The full trial is currently underway. [Crombie IK, Irvine L, Falconer DW, Williams B, Ricketts IW, Jones C, Humphris G, Norrie J, Slane P, Rice P. Alcohol and disadvantaged men: A feasibility trial of an intervention delivered by mobile phone. Drug Alcohol Rev 2017;36:468‐476]

Trial steering committees for randomised controlled trials: updating and redeveloping guidance and terms of reference informed by current practice and experience

The DAMOCLES project established a Data Monitoring Committee Charter which has been widely used for randomised controlled trials since 2005. As established within DAMOCLES, the DMC is typical advisory, making recommendations to another executive body; considered the Trial Steering Committee. No evidence-based Charter exists for TSCs to establish their role and functionality in RCTs. n nThe MRC Guidelines for Good Clinical Practice (1998) defines a three committee oversight structure: the day-to-day Trial Management Group, the DMC and the executive TSC. The document provides brief Terms of Reference for TSCs and represents the first attempt at guidance on TSC remit and structure. It is not known whether or how extensively this document has been used to inform TSC-like current roles and practice. There is acknowledged variation in practice in the UK and, moreover, internationally. n nThe aim of this project was to re-visit the MRC Terms of Reference and provide dedicated guidance on TSC remit and structure by producing a comprehensive Terms of Reference and Charter that will promote a systematic and transparent approach to the oversight of RCTs. n nTo inform this development, a survey to establish current practice and requirements within UK registered Clinical Trials Units has been undertaken. A cohort of published RCTs within medical journals and HTA monographs has been obtained to determine how TSC activities are currently reported and the literature reviewed to identify case studies of TSC activity in RCT conduct. n nResults of this work will be presented with how these findings impact development of more complete guidelines.

Male synthetic sling versus artificial urinary sphincter trial for men with urodynamic stress incontinence after prostate surgery (MASTER) : Study protocol for a randomised controlled trial

BackgroundStress urinary incontinence (SUI) is a frequent adverse effect for men undergoing prostate surgery. A large proportion (around 8% after radical prostatectomy and 2% after transurethral resection of prostate (TURP)) are left with severe disabling incontinence which adversely effects their quality of life and many are reliant on containment measures such as pads (27% and 6% respectively). Surgery is currently the only option for active management of the problem.The overwhelming majority of surgeries for persistent bothersome SUI involve artificial urinary sphincter (AUS) insertion. However, this is expensive, and necessitates manipulation of a pump to enable voiding. More recently, an alternative to AUS has been developed – a synthetic sling for men which elevates the urethra, thus treating SUI. This is thought, by some, to be less invasive, more acceptable and less expensive than AUS but clear evidence for this is lacking.The MASTER trial aims to determine whether the male synthetic sling is non-inferior to implantation of the AUS for men who have SUI after prostate surgery (for cancer or benign disease), judged primarily on clinical effectiveness but also considering relative harms and cost-effectiveness.Methods/designMen with urodynamic stress incontinence (USI) after prostate surgery, for whom surgery is judged appropriate, are the target population. We aim to recruit men from secondary care urological centres in the UK NHS who carry out surgery for post-prostatectomy incontinence. Outcomes will be assessed by participant-completed questionnaires and 3-day urinary bladder diaries at baseline, 6, 12 and 24 months. The 24-h urinary pad test will be used at baseline as an objective assessment of urine loss. Clinical data will be completed at the time of surgery to provide details of the operative procedures, complications and resource use in hospital. At 12 months, men will also have a clinical review to evaluate the results of surgery (including another 24-h pad test) and to identify problems or need for further treatment.DiscussionA robust examination of the comparative effectiveness of the male synthetic sling will provide high-quality evidence to determine whether or not it should be adopted widely in the NHS.Trial registrationInternational Standard Randomised Controlled Trial Registry: Number ISRCTN49212975. Registered on 22 July 2013. First patient randomised on 29 January 2014.

HEALTH: laparoscopic supracervical hysterectomy versus second-generation endometrial ablation for the treatment of heavy menstrual bleeding: study protocol for a randomised controlled trial

BackgroundHeavy menstrual bleeding (HMB) is a common problem affecting approximately 1.5 million women in England and Wales with a major impact on their physical, emotional, social and material quality of life. It is the fourth most common reason why women attend gynaecology outpatient clinics and accounts for one-fifth of all gynaecology outpatient referrals. Initial treatment in primary care is medical - either by means of oral or injected medication or the levonorgestrel-intrauterine system (Mirena®). If medical treatment fails then surgical treatment can be offered, either endometrial ablation (EA), which destroys the lining of the cavity of the uterus (endometrium), or hysterectomy, i.e. surgical removal of the uterus.While effective, conventional hysterectomy is invasive and carries a risk of complications due to injury to other pelvic structures. The procedure can be simplified and complications minimised by undertaking a ‘supracervical’ hysterectomy where the cervix is left in situ and only the body of the uterus removed. Recent advances in endoscopic technologies have facilitated increased use of laparoscopic supracervical hysterectomy (LASH) which can be performed as a day-case procedure and is relatively easy for the surgeon to learn.HEALTH (Hysterectomy or Endometrial AbLation Trial for Heavy menstrual bleeding) aims to address the question ‘Is LASH superior to second generation EA for the treatment of HMB in terms of clinical and cost effectiveness?’Methods/DesignWomen agedu2009<u200950xa0years, with HMB, in whom medical treatment has failed and who are eligible for EA will be considered for trial entry. We aim to recruit women from approximately 30 active secondary care centres in the UK NHS who carry out both surgical procedures. All women who consent will complete a diary of pain symptoms from day 1 to day 14 after surgery, postal questionnaires at six weeks and six months after surgery and 15xa0months post randomisation. Healthcare utilisation questions will also be completed at the six-week, six-month and 15-month time-points.DiscussionMeasuring the comparative effectiveness of LASH vs EA will provide the robust evidence required to determine whether the new technique should be adopted widely in the NHS.Trial registrationInternational Standard Randomised Controlled Trials, ISRCTN49013893. Registered on 28 January 2014.

Cognitive behavioural therapy in clozapine-resistant schizophrenia (FOCUS): an assessor-blinded, randomised controlled trial

Summary Background Although clozapine is the treatment of choice for treatment-refractory schizophrenia, 30–40% of patients have an insufficient response, and others are unable to tolerate it. Evidence for any augmentation strategies is scarce. We aimed to determine whether cognitive behavioural therapy (CBT) is an effective treatment for clozapine-resistant schizophrenia. Methods We did a pragmatic, parallel group, assessor-blinded, randomised controlled trial in community-based and inpatient mental health services in five sites in the UK. Patients with schizophrenia who were unable to tolerate clozapine, or whose symptoms did not respond to the drug, were randomly assigned 1:1 by use of randomised-permuted blocks of size four or six, stratified by centre, to either CBT plus treatment as usual or treatment as usual alone. Research assistants were masked to allocation to protect against rater bias and allegiance bias. The primary outcome was the Positive and Negative Syndrome Scale (PANSS) total score at 21 months, which provides a continuous measure of symptoms of schizophrenia; PANSS total was also assessed at the end of treatment (9 months). The primary analysis was by randomised treatment based on intention to treat, for all patients for whom data were available. This study was prospectively registered, number ISRCTN99672552. The trial is closed to accrual. Findings From Jan 1, 2013, to May 31, 2015, we randomly assigned 487 participants to either CBT and treatment as usual (n=242) or treatment as usual alone (n=245). Analysis included 209 in the CBT group and 216 in the treatment as usual group. No difference occurred in the primary outcome (PANSS total at 21 months, mean difference −0·89, 95% CI −3·32 to 1·55; p=0·48), although the CBT group improved at the end of treatment (PANSS total at 9 months, mean difference −2·40, −4·79 to −0·02; p=0·049). During the trial, 107 (44%) of 242 participants in the CBT arm and 104 (42%) of 245 in the treatment as usual arm had at least one adverse event (odds ratio 1·09, 95% CI 0·81 to 1·46; p=0·58). Only two (1%) of 242 participants in the CBT arm and one (<1%) of 245 in the treatment as usual arm had a trial-related serious adverse event. Interpretation At 21-month follow-up, CBT did not have a lasting effect on total symptoms of schizophrenia compared with treatment as usual; however, CBT produced statistically, though not clinically, significant improvements on total symptoms by the end of treatment. There was no indication that the addition of CBT to treatment as usual caused adverse effects. The results of this trial do not support a recommendation to routinely offer CBT to all people who meet criteria for clozapine-resistant schizophrenia; however, a pragmatic individual trial might be indicated for some. Funding National Institute for Health Research Technology Assessment programme.

Oral Ketamine vs Placebo in Patients With Cancer-Related Neuropathic Pain: A Randomized Clinical Trial.

This multicenter randomized clinical trial compares oral ketamine with placebo for treating neuropathic pain in patients with cancer.

Texting to Reduce Alcohol Misuse (TRAM) : main findings from a randomized controlled trial of a text message intervention to reduce binge drinking among disadvantaged men

AIMSnTo test the effectiveness of a theoretically based text-message intervention to reduce binge drinking among socially disadvantaged men.nnnDESIGNnA multi-centre parallel group, pragmatic, individually randomized controlled trial.nnnSETTINGnCommunity-based study conducted in four regions of Scotland.nnnPARTICIPANTSnA total of 825 men aged 25-44xa0years recruited from socially disadvantaged areas who had two or more episodes of binge drinking (>xa08 UK units on a single occasion) in the preceding 28xa0days: 411 men were randomized to the intervention and 414 to the control.nnnINTERVENTION AND COMPARATORnA series of 112 interactive text messages was delivered by mobile phone during a 12-week period. The intervention was structured around the Health Action Process Approach, a comprehensive model which allows integration of a range of evidence-based behaviour change techniques. The control group received 89 texts on general health, with no mention of alcohol or use of behaviour change techniques.nnnMEASUREMENTSnThe primary outcome measure was the proportion of men consuming >xa08xa0units on three or more occasions (in the previous 28xa0days) at 12xa0months post-intervention.nnnFINDINGSnThe proportion of men consuming >xa08xa0units on three or more occasions (in the previous 28xa0days) was 41.5% in the intervention group and 47.8% in the control group. Formal analysis showed that there was no evidence that the intervention was effective [odds ratio (OR)xa0=xa00.79, 95% confidence interval (CI)xa0=xa00.57-1.08; absolute reduction 5.7%, 95% CIxa0=xa0-13.3 to 1.9]. The Bayes factor for this outcome was 1.3, confirming that the results were inconclusive. The retention was high and similar in intervention (84.9%) and control (86.5%) groups. Most men in the intervention group engaged with the text messages: almost all (92%) replied to text messages and 67% replied more than 10 times.nnnCONCLUSIONSnA theoretically based text-messaging intervention aimed at reducing binge drinking in disadvantaged men was not found to reduce prevalence of binge drinking at 12-month follow-up.

TISU: Extracorporeal shockwave lithotripsy, as first treatment option, compared with direct progression to ureteroscopic treatment, for ureteric stones: study protocol for a randomised controlled trial

BackgroundUrinary stone disease is very common with an estimated prevalence among the general population of 2–3%. Ureteric stones are associated with severe pain as they pass through the urinary tract and have significant impact on patients’ quality of life due to the detrimental effect on their ability to work and need for hospitalisation. Most ureteric stones can be expected to pass spontaneously with supportive care. However, between one-fifth and one-third of cases require an intervention.The two standard active intervention options are extracorporeal shockwave lithotripsy (ESWL) and ureteroscopic stone retrieval. ESWL and ureteroscopy are effective in terms of stone clearance; however, they differ in terms of invasiveness, anaesthetic requirement, treatment setting, complications, patient-reported outcomes (e.g. pain after intervention, time off work) and cost. There is uncertainty around which is the most clinically effective in terms of stone clearance and the true cost to the NHS and to society (in terms of impact on patient-reported health and economic burden).The aim of this trial is to determine whether, in adults with ureteric stones, judged to require active intervention, ESWL is not inferior and is more cost-effective compared to ureteroscopic treatment as the initial management option.MethodsThe TISU study is a pragmatic multicentre non-inferiority randomised controlled trial of ESWL as the first treatment option compared with direct progression to ureteroscopic treatment for ureteric stones.Patients aged over 16 years with a ureteric stone confirmed by non-contrast computed tomography of the kidney, ureter and bladder (CTKUB) will be randomised to either ESWL or ureteroscopy. The primary clinical outcome is resolution of the stone episode (no further intervention required to facilitate stone clearance) up to six months from randomisation. The primary economic outcome is the incremental cost per quality-adjusted life years (QALYs) gained at sixxa0months from randomisation.DiscussionDetermining whether ESWL is not inferior clinically and is cost-effective compared to ureteroscopic treatment as the initial management in adults with ureteric stones who are judged to require active treatment is relevant not only to patients and clinicians but also to healthcare providers, both in the UK and globally.Trial registrationISRCTN registry, ISRCTN92289221. Registered on 21 February 2013.

Improving the Quality of Dentistry (IQuaD) : a cluster factorial randomised controlled trial comparing the effectiveness and cost-benefit of oral hygiene advice and/or periodontal instrumentation with routine care for the prevention and management of periodontal disease in dentate adults attending dental primary care

BACKGROUNDnPeriodontal disease is preventable but remains the most common oral disease worldwide, with major health and economic implications. Stakeholders lack reliable evidence of the relative clinical effectiveness and cost-effectiveness of different types of oral hygiene advice (OHA) and the optimal frequency of periodontal instrumentation (PI).nnnOBJECTIVESnTo test clinical effectiveness and assess the economic value of the following strategies: personalised OHA versus routine OHA, 12-monthly PI (scale and polish) compared with 6-monthly PI, and no PI compared with 6-monthly PI.nnnDESIGNnMulticentre, pragmatic split-plot, randomised open trial with a cluster factorial design and blinded outcome evaluation with 3 years follow-up and a within-trial cost-benefit analysis. NHS and participant costs were combined with benefits [willingness to pay (WTP)] estimated from a discrete choice experiment (DCE).nnnSETTINGnUK dental practices.nnnPARTICIPANTSnAdult dentate NHS patients, regular attenders, with Basic Periodontal Examination (BPE) scores of 0, 1, 2 or 3.nnnINTERVENTIONnPractices were randomised to provide routine or personalised OHA. Within each practice, participants were randomised to the following groups: no PI, 12-monthly PI or 6-monthly PI (current practice).nnnMAIN OUTCOME MEASURESnClinical - gingival inflammation/bleeding on probing at the gingival margin (3 years). Patient - oral hygiene self-efficacy (3 years). Economic - net benefits (mean WTP minus mean costs).nnnRESULTSnA total of 63 dental practices and 1877 participants were recruited. The mean number of teeth and percentage of bleeding sites was 24 and 33%, respectively. Two-thirds of participants had BPE scores of ≤ 2. Under intention-to-treat analysis, there was no evidence of a difference in gingival inflammation/bleeding between the 6-monthly PI group and the no-PI group [difference 0.87%, 95% confidence interval (CI) -1.6% to 3.3%; pu2009=u20090.481] or between the 6-monthly PI group and the 12-monthly PI group (difference 0.11%, 95% CI -2.3% to 2.5%; pu2009=u20090.929). There was also no evidence of a difference between personalised and routine OHA (difference -2.5%, 95% CI -8.3% to 3.3%; pu2009=u20090.393). There was no evidence of a difference in self-efficacy between the 6-monthly PI group and the no-PI group (difference -0.028, 95% CI -0.119 to 0.063; pu2009=u20090.543) and no evidence of a clinically important difference between the 6-monthly PI group and the 12-monthly PI group (difference -0.097, 95% CI -0.188 to -0.006; pu2009=u20090.037). Compared with standard care, no PI with personalised OHA had the greatest cost savings: NHS perspective -£15 (95% CI -£34 to £4) and participant perspective -£64 (95% CI -£112 to -£16). The DCE shows that the general population value these services greatly. Personalised OHA with 6-monthly PI had the greatest incremental net benefit [£48 (95% CI £22 to £74)]. Sensitivity analyses did not change conclusions.nnnLIMITATIONSnBeing a pragmatic trial, we did not deny PIs to the no-PI group; there was clear separation in the mean number of PIs between groups.nnnCONCLUSIONSnThere was no additional benefit from scheduling 6-monthly or 12-monthly PIs over not providing this treatment unless desired or recommended, and no difference between OHA delivery for gingival inflammation/bleeding and patient-centred outcomes. However, participants valued, and were willing to pay for, both interventions, with greater financial value placed on PI than on OHA.nnnFUTURE WORKnAssess the clinical effectiveness and cost-effectiveness of providing multifaceted periodontal care packages in primary dental care for those with periodontitis.nnnTRIAL REGISTRATIONnCurrent Controlled Trials ISRCTN56465715.nnnFUNDINGnThis project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 38. See the NIHR Journals Library website for further project information.