Search

Objectives To estimate the cost-effectiveness of methenamine hippurate compared with antibiotic prophylaxis in the management of recurrent urinary tract infections.Design Multicentre, open-label, randomised, non-inferiority trial.Setting Eight centres in the UK, recruiting from June 2016 to June 2018.Participants Women aged ≥18 years with recurrent urinary tract infections, requiring prophylactic treatment.Interventions Women were randomised to receive once-daily antibiotic prophylaxis or twice-daily methenamine hippurate for 12 months. Treatment allocation was not masked and crossover between arms was allowed.Primary and secondary outcome measures The primary economic outcome was the incremental cost per quality-adjusted life year (QALY) gained at 18 months. All costs were collected from a UK National Health Service perspective. QALYs were estimated based on responses to the EQ-5D-5L administered at baseline, 3, 6, 9, 12 and 18 months. Incremental costs and QALYs were estimated using an adjusted analysis which controlled for observed and unobserved characteristics. Stochastic sensitivity analysis was used to illustrate uncertainty on a cost-effectiveness plane and a cost-effectiveness acceptability curve. A sensitivity analysis, not specified in the protocol, considered the costs associated with antibiotic resistance.Results Data on 205 participants were included in the economic analysis. On average, methenamine hippurate was less costly (−£40; 95% CI: −684 to 603) and more effective (0.014 QALYs; 95% CI: −0.05 to 0.07) than antibiotic prophylaxis. Over the range of values considered for an additional QALY, the probability of methenamine hippurate being considered cost-effective ranged from 51% to 67%.Conclusions On average, methenamine hippurate was less costly and more effective than antibiotic prophylaxis but these results are subject to uncertainty. Methenamine hippurate is more likely to be considered cost-effective when the benefits of reduced antibiotic use were included in the analysis.Trial registration number ISRCTN70219762.

Background The indications for septoplasty are practice-based, rather than evidence-based. In addition, internationally accepted guidelines for the management of nasal obstruction associated with nasal septal deviation are lacking. Objective The objective was to determine the clinical effectiveness and cost-effectiveness of septoplasty, with or without turbinate reduction, compared with medical management, in the management of nasal obstruction associated with a deviated nasal septum. Design This was a multicentre randomised controlled trial comparing septoplasty, with or without turbinate reduction, with defined medical management; it incorporated a mixed-methods process evaluation and an economic evaluation. Setting The trial was set in 17 NHS secondary care hospitals in the UK. Participants A total of 378 eligible participants aged > 18 years were recruited. Interventions Participants were randomised on a 1: 1 basis and stratified by baseline severity and gender to either (1) septoplasty, with or without turbinate surgery (n = 188) or (2) medical management with intranasal steroid spray and saline spray (n = 190). Main outcome measures The primary outcome was the Sino-nasal Outcome Test-22 items score at 6 months (patient-reported outcome). The secondary outcomes were as follows: patient-reported outcomes – Nasal Obstruction Symptom Evaluation score at 6 and 12 months, Sino-nasal Outcome Test-22 items subscales at 12 months, Double Ordinal Airway Subjective Scale at 6 and 12 months, the Short Form questionnaire-36 items and costs; objective measurements – peak nasal inspiratory flow and rhinospirometry. The number of adverse events experienced was also recorded. A within-trial economic evaluation from an NHS and Personal Social Services perspective estimated the incremental cost per (1) improvement (of ≥ 9 points) in Sino-nasal Outcome Test-22 items score, (2) adverse event avoided and (3) quality-adjusted life-year gained at 12 months. An economic model estimated the incremental cost per quality-adjusted life-year gained at 24 and 36 months. A mixed-methods process evaluation was undertaken to understand/address recruitment issues and examine the acceptability of trial processes and treatment arms. Results At the 6-month time point, 307 participants provided primary outcome data (septoplasty, n = 152; medical management, n = 155). An intention-to-treat analysis revealed a greater and more sustained improvement in the primary outcome measure in the surgical arm. The 6-month mean Sino-nasal Outcome Test-22 items scores were −20.0 points lower (better) for participants randomised to septoplasty than for those randomised to medical management [the score for the septoplasty arm was 19.9 and the score for the medical management arm was 39.5 (95% confidence interval −23.6 to −16.4; p < 0.0001)]. This was confirmed by sensitivity analyses and through the analysis of secondary outcomes. Outcomes were statistically significantly related to baseline severity, but not to gender or turbinate reduction. In the surgical and medical management arms, 132 and 95 adverse events occurred, respectively; 14 serious adverse events occurred in the surgical arm and nine in the medical management arm. On average, septoplasty was more costly and more effective in improving Sino-nasal Outcome Test-22 items scores and quality-adjusted life-years than medical management, but incurred a larger number of adverse events. Septoplasty had a 15% probability of being considered cost-effective at 12 months at a £20,000 willingness-to-pay threshold for an additional quality-adjusted life-year. This probability increased to 99% and 100% at 24 and 36 months, respectively. Limitations COVID-19 had an impact on participant-facing data collection from March 2020. Conclusions Septoplasty, with or without turbinate reduction, is more effective than medical management with a nasal steroid and saline spray. Baseline severity predicts the degree of improvement in symptoms. Septoplasty has a low probability of cost-effectiveness at 12 months, but may be considered cost-effective at 24 months. Future work should focus on developing a septoplasty patient decision aid. Trial registration This trial is registered as ISRCTN16168569 and EudraCT 2017-000893-12. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 14/226/07) and is published in full in Health Technology Assessment; Vol. 28, No. 10. See the NIHR Funding and Awards website for further award information. Plain language summary Septoplasty is an operation to straighten the septum, which is the partition wall between the nostrils inside the nose. Septoplasty can be used as a treatment for people who have a bent septum and symptoms of a blocked nose, such as difficulty sleeping and exercising. Medical management (a saltwater spray to clear the nose followed by a nose steroid spray) is an alternative treatment to septoplasty. The Nasal AIRway Obstruction Study (NAIROS) aimed to find out whether septoplasty or medical management is a better treatment for people with a bent septum and symptoms of a blocked nose. We recruited 378 patients with at least moderately severe nose symptoms from 17 hospitals in England, Scotland and Wales to take part in the NAIROS. Participants were randomly put into one of two groups: septoplasty or medical management. Participants’ nose symptoms were measured both when they joined the study and after 6 months, using a questionnaire called the Sino-nasal Outcome Test-22 items. This questionnaire was chosen because patients reported that it included symptoms that were important to them. Other studies have shown that a 9-point change in the Sino-nasal Outcome Test-22 items score is significant. After 6 months, on average, people in the septoplasty group improved by 25 points, whereas people in the medical management group improved by 5 points. We saw improvement after septoplasty among patients with moderate symptoms, and among those with severe symptoms. Most patients who we spoke to after a septoplasty were happy with their treatment, but some would have liked more information about what to expect after their nose surgery. In the short term, septoplasty is more costly than medical management. However, over the longer term, taking into account all the costs and benefits of treatment, suggests that septoplasty would be considered good value for money for the NHS. Scientific summary Background The indications for septoplasty are practice-based, rather than evidence-based. In addition, internationally accepted guidelines for the management of nasal obstruction associated with nasal septal deviation are lacking. Objectives The study objectives are split into three different aspects: clinical effectiveness, economic evaluation and mixed-methods process evaluation. Objective 1 was to measure clinical effectiveness according to: subjective self-reported rating of nasal airway obstruction heterogeneity of estimated treatment effect, specifically according to severity of obstruction and gender objective measures of nasal patency number of adverse events (AEs) and additional interventions required technical failure in the surgical arm how well those agreeing to enter the trial reflect those screened for eligibility. Objective 2 was to conduct an economic evaluation from the perspective of the NHS and Personal Social Services. This entailed the following processes: conducting a cost-effectiveness analysis, with outcomes reported as incremental cost per ≥ 9-point improvement in the Sino-nasal Outcome Test-22 items (SNOT-22) scores and number of AEs conducting a cost–utility analysis, with outcomes reported as incremental cost per quality-adjusted life-year (QALY) gained designing a longer-term economic model to assess costs and health consequences beyond the 12-month follow-up period. Objective 3 was to conduct a mixed-methods process evaluation of the trial and interventions, to understand: barriers to optimal recruitment, and potential solutions to address these, through integration of the Qualitative research integrated within Trials (QuinteT) Recruitment Intervention (QRI) participants’ and healthcare professionals’ experiences of trial participation and the interventions, and perceived factors likely to influence wider implementation of trial findings. Methods The Nasal AIRway Obstruction Study (NAIROS) was a multicentre, non-blinded randomised controlled trial comparing the effectiveness of septoplasty, with or without turbinate surgery, with a standardised medical management package of 6 months of intranasal steroid spray and saline spray. Participants were randomised on a 1 : 1 basis between the septoplasty (within 8 weeks) and medical management arms. The trial included an integrated health economic evaluation and a mixed-methods process evaluation incorporating a QRI. The target sample size of 378 participants allowed for 20% dropout to deliver 90% power for detecting a minimal clinically important difference of 9 points in SNOT-22 scores. This assumed a two-sided type error rate of 5% and a standard deviation of 24 points in SNOT-22 scores at 6 months. Interventions The two interventions being compared were as follows. Septoplasty, with or without inferior turbinate reduction in the contralateral nostril, performed at the discretion of the investigating clinician, preferably performed within 8 weeks of randomisation or, if not, by 12 weeks. Medical management with 6 months of mometasone furoate 50 μg per dose nasal steroid spray, suspension (Nasonex®; Merck Sharp & Dohme Limited, Hoddesdon, UK), and isotonic nasal saline spray. Participants had the option of deferred surgery after 6 or 12 months post randomisation. Setting and participants We recruited 378 patients to the main trial from 17 NHS hospitals in Great Britain. Eligible patients were identified from general ear, nose and throat referrals. Of those recruited, 188 were randomised to septoplasty and 190 were randomised to medical management. Inclusion criteria Adults aged ≥ 18 years. Baseline Nasal Obstruction Symptom Evaluation (NOSE) scale score of ≥ 30. Septal deflection visible via nasoendoscopy. Capacity to provide informed consent/complete trial questionnaires. Exclusion criteria Prior septal surgery. Systemic inflammatory disease/use of oral steroid treatment in the previous 2 weeks. Granulomatosis with polyangiitis. Nasoendoscopic evidence of unrelated associated pathology. Intranasal recreational drug use in the previous 6 months. Breastfeeding, pregnancy or intended pregnancy for duration of involvement in the trial. Bleeding diathesis. Therapeutic anticoagulation. Contraindication to general anaesthesia. Immunocompromised. External bony deformity. Measurement of clinical outcomes Primary outcome The primary outcome was patient-reported assessment of nasal and general symptoms, using the SNOT-22 questionnaire, at 6 months (−2 weeks/+4 weeks). The SNOT-22 was also assessed at baseline and 12 months (± 2 weeks). Secondary outcomes Objective measures: peak nasal inspiratory flow and rhinospirometry (maximal inhalation volume and tidal breathing) at baseline and at 6 and 12 months. Patient-reported outcomes: SNOT-22 subscales at 12 months, NOSE score and Double Ordinal Airway Subjective Scale at baseline and at 6 and 12 months. Safety measures: number and characteristics of any AEs, surgical complications and reinterventions within 12 months. Quality of life, measured using the Short Form questionnaire-36 items (SF-36) at baseline and at 6 and 12 months. Healthcare utilisation questionnaire at baseline and at 6 and 12 months. Time and travel questionnaire at 12 months. Measurement of health economic outcomes To compare costs incurred by the NHS and Personal Social Services (PSS) with those incurred by participants in the management of a deviated septum. To compare QALYs, based on responses to the SF-36 administered at baseline and at 6 and 12 months, converted to Short Form questionnaire-6 Dimensions (SF-6D) utility scores, derived using the area under the curve method. To compare the cost-effectiveness of septoplasty with that of medical management at 12 months, measured in terms of the incremental: cost per improvement (of ≥ 9 points) in SNOT-22 scores cost per AE avoided cost per QALY gained. To compare the cost-effectiveness of septoplasty with that of medical management at 24 and 36 months in terms of the incremental cost per QALY gained (costs and QALYs were extrapolated using an economic model). Mixed-methods process evaluation outcomes The objectives for the mixed-methods process evaluation were addressed through observations of training and NAIROS meetings, interviews with health professionals and participants, audio-recording of recruitment discussions and review of screening logs. The QRI initiated with a ‘pre-recruitment’ phase to raise awareness about common recruitment issues/solutions learnt from previous trials. Phase 1 of the QRI investigated sources of recruitment difficulty that were specific to the NAIROS, informing ‘actions’ to optimise recruitment as the trial was under way (phase 2). Statistical analysis The primary statistical analysis was carried out on an intention-to-treat (ITT) basis, retaining patients in their randomised treatment groups. Multivariable linear regression models were used to compare the 6-month SNOT-22 scores between the treatment groups, adjusting any treatment effect by baseline SNOT-22 score and stratification factors at randomisation [(1) gender and (2) severity at baseline (according to three NOSE categories reported in the literature: 30–50, moderate; 55–75, severe; and 80–100, extreme)]. Sensitivity analyses, including a per-treatment and a per-protocol analysis, were also undertaken. Secondary outcomes were analysed in a way that was similar to the primary outcome analysis. Economic analysis The cost-effectiveness of septoplasty, compared with medical management, was evaluated by estimating the total costs incurred by the NHS and PSS to manage a deviated septum and averaging these costs across participants in each study arm. Both within-trial and model-based analyses were undertaken. The within-trial analysis estimated costs and effects over 12 months. Three different measures of effects were used: improvement (of ≥ 9 points) in SNOT-22 scores, number of AEs and QALYs. QALYs were derived from responses to the SF-36, which we converted into SF-6D scores (utilities) using a standardised algorithm and the area under the curve approach. An economic model was designed to extrapolate costs and benefits beyond the 12-month study follow-up period. Mixed-methods process evaluation analysis QuinteT Recruitment Intervention: thematic and content analyses were undertaken of interviews and audio-recorded consultations, and descriptive analyses of screening log data were undertaken. Qualitative process evaluation: a thematic analysis was undertaken using a coding framework, informed by normalisation process theory. Results Primary outcomes The ITT analysis found that, at 6 months, participants randomised to the septoplasty arm (n = 152) had SNOT-22 scores that were, on average, 20.0 points lower (i.e. better) than those of participants randomised to medical management (n = 155) [95% confidence interval (CI) −23.6 to −16.4 points; p < 0.0001]. This strong signal was confirmed by both sensitivity analyses and analysis of secondary outcomes. The mean SNOT-22 scores at 6 months were 19.9 points for the septoplasty arm and 39.5 points for the medical management arm. At 12 months, the adjusted mean difference for SNOT-22 scores between the two arms had reduced to −10.1 points (95% CI −14.5 to −5.6 points; p < 0.0001). This diminished effect at 12 months was predominantly due to SNOT-22 scores tending to reduce over time among those randomised to medical management. Overall, the improvement in SNOT-22 score in the surgical arm was both notably faster and greater, and was sustained over the trial period. Increased baseline severity of nasal obstruction was associated with greater improvements in the primary outcome. Gender had no impact on outcome improvement. Approximately 45 out of 190 (24%) participants discontinued allocated medical management treatment and had non-trial surgery, and 22 out of 188 (12%) of those randomised to septoplasty did not receive the surgical intervention. The per-protocol (treatment effect −19.7, 95% CI −23.4 to −16.0) and per-treatment analyses (treatment effect −19.3, 95% CI −23.3 to −15.3) confirmed a statistically significant greater improvement in the surgical arm. Secondary outcomes All secondary outcome measures, both patient-reported and objective measures, showed a greater improvement in the surgical arm. Turbinate reduction did not appear to add additional benefit in comparison with septoplasty alone. At 6 months, 80% of patients reported improvement in nasal breathing (74% at 12 months). Six out of 166 patients undergoing septoplasty were recommended to consider revision septoplasty. Adverse events Overall, there were 227 AEs: 132 in the surgical arm and 95 in the medical management arm. Fourteen serious adverse events occurred in the surgical arm and nine in the medical arm. At 6 months, 7 out of 174 (4%) participants experienced hospital re-admission with nasal bleeding, none of whom required operative reintervention. Twenty out of 172 (12%) participants reported infection requiring antibiotic treatment, 19 out of 171 (11%) participants reported decreased sense of smell, 18 out of 171 (11%) participants reported numbness of the upper teeth and 17 out of 171 (10%) participants reported change in appearance of the nose. Six nasal septal perforations (3%) and seven intranasal adhesions (4%) were noted at 6 and 12 months’ follow-up. Economic evaluation On average, septoplasty was more costly and more effective in terms of improvements in SNOT-22 score and QALYs than medical management. The incremental cost per improvement (of ≥ 9 points) in SNOT-22 score was £4855. The incremental cost per QALY gained was £27,114 and septoplasty had a 15% probability of being considered cost-effective at a £20,000 willingness-to-pay threshold for an additional QALY. This probability increased to 68% at a £30,000 threshold. Septoplasty was dominated by medical management when AEs were the outcome of interest, as it was more costly and associated with a greater number of AEs. The economic model estimated the incremental cost per QALY gained at 24 months (£13,221) and 36 months (£7368). Septoplasty had a 99% (at 24 months) and a 100% (at 36 months) probability of being considered cost-effective, compared with medical management, at a £20,000 threshold for an additional QALY. Mixed-methods process evaluation QuinteT Recruitment Intervention findings Data sources included 19 interviews with recruiters, 108 audio-recorded discussions and regular scrutiny of screening logs. Despite recruiters’ commitment to the NAIROS, there were challenges operationalising recruitment processes into routine clinical care, which restricted identification of potentially eligible patients. Analysis of recorded consultations revealed evidence of recruiters operationalising the pre-recruitment training, but also illuminated unanticipated challenges around explaining the trial arms, which undermined equipoise. Tailored actions were implemented in phase 2 to address these issues, through feedback/training for individuals/groups, ‘recruitment workshops’ with sites, and written guidance and webinars for professionals who interacted with patients throughout the clinical pathway. The recruitment target was reached successfully without a funding extension and without the need to open additional sites. Qualitative process evaluation Nine surgeons and five research nurses working on the NAIROS trial were interviewed and 39 interviews were conducted with 31 participants. Prior to the NAIROS, decisions regarding the appropriateness of surgery for individual patients were made on the basis of a complex and largely subjective combination of symptoms, history and patient anatomy. Surgeons indicated that they would welcome clearer criteria to guide decision-making. However, although some surgeons embraced a role for standardised outcome measures such as the NOSE and the SNOT-22 in decision-making, others were more reluctant; this could be a barrier to the implementation of trial findings. Although trial findings show that, as a group, participants in the surgical arm experienced more improvement than those in the medical management arm, the qualitative study demonstrated that individual experiences were varied. Although some patients in the medical management arm achieved little or no benefit from treatment, others did report positive effects, with a possible mechanism of action being a reduction in turbinate size. Patients undergoing medical management might benefit from individual advice regarding application of the sprays, taking into account distorted anatomy, to maximise effectiveness and reduce side effects. Although most participants were able to incorporate spray use into their daily routines, long-term spray use was perceived by some to be burdensome. Despite the large number of participants who perceived septoplasty to be effective in reducing their symptoms, there were still some participants who felt that they received little to no benefit from the operation. Participants reported being underprepared for the immediate post-surgery period. Limitations COVID-19 had a major impact on the study, resulting in the cessation of clinical measurements and objective outcomes from March 2020. From that time, all patient-reported outcomes were collected by post or online, or transcribed over the telephone. The ITT analysis is likely to offer an overestimate of the true impact of medical management in improving outcomes as 22% of participants in that arm received septoplasty before the 12-month outcome point. Conclusions Septoplasty, with or without turbinate reduction, is a clinically effective intervention. Participants with a deviated nasal septum with a moderate, severe or extreme baseline severity of nasal obstruction symptoms had an improvement in patient-reported outcomes at 6 and 12 months. This improvement surpassed that of standardised medical management. The results suggest that surgery has a low probability of being cost-effective at 12 months but may be considered cost-effective at 24 months. Impact on health services The NAIROS clearly demonstrates that adults presenting with nasal obstruction associated with a deviated nasal septum, in the absence of clinical evidence of a coexistent nasal/sinus disease and with a baseline NOSE score of > 30, can reliably be offered surgery in the knowledge that improvements in patient-reported outcomes are superior to improvements when treated with a nasal steroid/saline spray combination. Recommendations for research The most important research priority to emerge from the NAIROS is the need to develop a patient decision aid to explore management of a deviated nasal septum. The place of medical treatment in the management of nasal obstruction associated with a deviated nasal septum needs to be explored further. A prospective randomised trial would be required to examine the place of turbinate reduction surgery in nasal obstruction. Study registration This trial is registered as ISRCTN16168569 and EudraCT 2017-000893-12. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 14/226/07) and is published in full in Health Technology Assessment; Vol. 28, No. 10. See the NIHR Funding and Awards website for further award information.

Background The place of tonsillectomy in the management of sore throat in adults remains uncertain. Objectives To establish the clinical effectiveness and cost-effectiveness of tonsillectomy, compared with conservative management, for tonsillitis in adults, and to evaluate the impact of alternative sore throat patient pathways. Design This was a multicentre, randomised controlled trial comparing tonsillectomy with conservative management. The trial included a qualitative process evaluation and an economic evaluation. Setting The study took place at 27 NHS secondary care hospitals in Great Britain. Participants A total of 453 eligible participants with recurrent sore throats were recruited to the main trial. Interventions Patients were randomised on a 1 : 1 basis between tonsil dissection and conservative management (i.e. deferred surgery) using a variable block-stratified design, stratified by (1) centre and (2) severity. Main outcome measures The primary outcome measure was the total number of sore throat days over 24 months following randomisation. The secondary outcome measures were the number of sore throat episodes and five characteristics from Sore Throat Alert Return, describing severity of the sore throat, use of medications, time away from usual activities and the Short Form questionnaire-12 items. Additional secondary outcomes were the Tonsil Outcome Inventory-14 total and subscales and Short Form questionnaire-12 items 6 monthly. Evaluation of the impact of alternative sore throat patient pathways by observation and statistical modelling of outcomes against baseline severity, as assessed by Tonsil Outcome Inventory-14 score at recruitment. The incremental cost per sore throat day avoided, the incremental cost per quality-adjusted life-year gained based on responses to the Short Form questionnaire-12 items and the incremental net benefit based on costs and responses to a contingent valuation exercise. A qualitative process evaluation examined acceptability of trial processes and ramdomised arms. Results There was a median of 27 (interquartile range 12–52) sore throats over the 24-month follow-up. A smaller number of sore throats was reported in the tonsillectomy arm [median 23 (interquartile range 11–46)] than in the conservative management arm [median 30 (interquartile range 14–65)]. On an intention-to-treat basis, there were fewer sore throats in the tonsillectomy arm (incident rate ratio 0.53, 95% confidence interval 0.43 to 0.65). Sensitivity analyses confirmed this, as did the secondary outcomes. There were 52 episodes of post-operative haemorrhage reported in 231 participants undergoing tonsillectomy (22.5%). There were 47 re-admissions following tonsillectomy (20.3%), 35 relating to haemorrhage. On average, tonsillectomy was more costly and more effective in terms of both sore throat days avoided and quality-adjusted life-years gained. Tonsillectomy had a 100% probability of being considered cost-effective if the threshold for an additional quality-adjusted life year was £20,000. Tonsillectomy had a 69% probability of having a higher net benefit than conservative management. Trial processes were deemed to be acceptable. Patients who received surgery were unanimous in reporting to be happy to have received it. Limitations The decliners who provided data tended to have higher Tonsillectomy Outcome Inventory-14 scores than those willing to be randomised implying that patients with a higher burden of tonsillitis symptoms may have declined entry into the trial. Conclusions The tonsillectomy arm had fewer sore throat days over 24 months than the conservative management arm, and had a high probability of being considered cost-effective over the ranges considered. Further work should focus on when tonsillectomy should be offered. National Trial of Tonsillectomy IN Adults has assessed the effectiveness of tonsillectomy when offered for the current UK threshold of disease burden. Further research is required to define the minimum disease burden at which tonsillectomy becomes clinically effective and cost-effective. Trial registration This trial is registered as ISRCTN55284102. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 12/146/06) and is published in full in Health Technology Assessment; Vol. 27, No. 31. See the NIHR Funding and Awards website for further award information. Plain language summary Tonsillectomy is an operation to take out the pair of tonsil glands at the back of the throat. It is an option for adults who suffer from repeated, severe sore throats. Adults who have a tonsillectomy say that they get fewer sore throats afterwards, but it is not clear whether or not they would have got better over time without the operation. There is pressure on doctors to limit the number of tonsillectomies carried out. At the same time, emergency hospital admissions for adults with severe throat infections have been increasing. NAtional Trial of Tonsillectomy IN Adults aimed to find out whether tonsillectomy is an effective and worthwhile treatment for repeated severe sore throats or whether patients would be better off treated without an operation. A total of 453 patients from 27 hospitals in Great Britain took part in the study. Patients were assigned at random to receive either tonsillectomy or conservative management (treatment as needed from their general practitioner). We measured how many sore throats patients had in the next 2 years by sending them text messages every week. We asked about the impact of their sore throats on their quality of life and time off work, and looked at the costs of treatment. We also interviewed 47 patients, general practitioners and hospital staff about their experiences of tonsillectomy and NAtional Trial of Tonsillectomy IN Adults. The typical patient in the tonsillectomy arm had 23 days of sore throat compared with 30 days of sore throat in the conservative management arm. Tonsillectomy resulted in higher quality of life. We looked to see whether or not it was only those with the most severe sore throats who benefited from tonsillectomy, but we found that patients with more or less severe sore throats at the start all did better with tonsillectomy. Patients who had a tonsillectomy were happy to have undertaken this. Our findings suggest a clear benefit of tonsillectomy using modest additional NHS resources for adults with repeated severe sore throats. Scientific summary Background Sore throats cost the NHS over £120M per annum, including ≈ £60M for general practitioner (GP) consultations and medical therapy. The place of tonsillectomy in the management of sore throat remains uncertain. Objectives Clinical To establish the clinical effectiveness of tonsillectomy, compared with conservative management, for tonsillitis in adults. To report the number of adverse events (AEs), visits to the GP/walk-in clinic/accident and emergency, prescriptions issued and additional interventions required to manage sore throats and related events through weekly Sore Throat Alert Return (STAR) response data and primary care patient records. To adjust the estimate of effectiveness in the light of other baseline covariates, including severity of tonsillitis. To evaluate the impact of alternative sore throat patient pathways by observation and statistical modelling of outcomes. To assess to what extent trial participants were representative of the total population of sore throat patients referred to ear, nose and throat (ENT) clinics. To inform future research. Qualitative process evaluation To examine the acceptability of the trial, treatments and unforeseen consequences from the perspective of participants and stakeholders, including ENT staff and GPs. Economic evaluation To compare costs incurred by the NHS, Personal and Social Services (PSS) and participants to manage recurrent sore throats in adults. To compare quality-adjusted life-years (QALYs) using the area-under-the-curve method based on Short Form questionnaire-6 Dimension (SF-6D) scores derived from longitudinal Short Form questionnaire-12 items (SF-12) responses throughout the study and during self-reported sore throat episodes. To compare the cost-effectiveness measured in terms of the incremental: cost per sore throat day avoided cost per QALY gained net benefit – estimated based on self-reported number of sore throat days and responses to a contingent valuation questionnaire administered at baseline asking participants’ willingness to pay (WTP) to avoid a sore throat day. Methods Design A multicentre, randomised controlled trial comparing the effectiveness of tonsillectomy for recurrent sore throat with that of non-surgical conservative management in a 1 : 1 ratio over a 24-month period. Surgeons, participants and site staff could not be blinded to the allocated procedure. The main trial began following the completion of a feasibility study and included a qualitative process evaluation, as well as an economic evaluation. The design, conduct and reporting of the trial were informed by patients. Crossover of participants between arms was permitted. Interventions Tonsil dissection: dissection of the palatine tonsils preferably within 6 weeks, and no more than 8 weeks, following randomisation (dissection method at the discretion of the participating centres). Conservative (non-surgical) management (i.e. deferred surgery): participants entering the conservative management arm were asked to defer surgery for up to 24 months on the understanding that they would be reviewed at 12 months. Setting and participants A total of 453 patients were recruited to the main trial from 27 NHS secondary care hospitals in Great Britain. Eligible patients were identified via general ENT referrals and established sore throat-specific referral pathways, some of which were run by ENT nurse practitioners. Inclusion criteria Aged ≥16 years. Recurrent sore throats that fulfil current Scottish Intercollegiate Guidelines Network (SIGN) guidance for elective tonsillectomy. Exclusion criteria Previous tonsillectomy. Listed directly (i.e. added to waiting list without prior elective ENT outpatient appointment) during emergency admission (e.g. owing to peritonsillar abscess/quinsy). Primary sleep breathing disorder. Suspected malignancy. Tonsilloliths (as primary referral). Pregnant or breastfeeding. Bleeding diathesis (including haemophilia, sickle cell disease and platelet dysfunction). Therapeutic anticoagulation. Inability to complete self-reported questionnaires and sore throat returns. Main outcome measures Primary outcome The primary outcome measure was the total number of sore throat days over the 24 months following randomisation. The number of sore throat days was collected by a database that was designed for use in the trial (the STAR database). This database allowed participants to respond weekly to alerts by providing the number of sore throats that they had experienced in the previous 7 days (between 0 and 7 sore throat days). From the beginning of the trial, participants were able to choose their preferred method for receiving these alerts: e-mail, text message or interactive voice response (IVR) via telephone. Secondary outcomes A participant who had suffered from a sore throat in the past week (i.e. sore throat days >0) was asked to provide information on the severity of the sore throat(s) and additional data for health economics and other secondary outcomes in a STAR questionnaire. Quality-of-life data, reported as the SF-12 physical component score (PCS) and mental component score (MCS) and additional symptoms of tonsillitis, were collected every 6 months. The impact of alternative NHS sore throat pathways was measured by observation and statistical modelling of outcomes. The extent to which trial participants represented the total population of sore throat patients referred to ENT clinics was assessed through analysis of site screening logs. Adverse events Information regarding the AEs related to the trial intervention was collected during telephone calls at 1 and 2 weeks post tonsillectomy; all tonsillectomy arm serious adverse events (SAEs) were recorded throughout the duration of the trial for all participants. Economic evaluation The cost-effectiveness of tonsillectomy compared with conservative management was evaluated by estimating the total costs incurred by the NHS and PSS, and averaging these costs across participants in each trial arm. Three different analyses were undertaken: (1) a cost-effectiveness analysis (CEA), (2) a cost–utility analysis (CUA) and (3) a cost–benefit analysis (CBA). All three analyses measured costs using the same methodology but differed in their measure of effectiveness. An incremental cost-effectiveness ratio was estimated for the CEA and the CUA by dividing the difference in average total costs by the difference in average total effects. The CEA estimated the incremental cost per sore throat day avoided. The number of sore throat days was derived from the primary outcome data. The CUA estimated the incremental cost per QALY gained. QALYs were derived using the SF-6D algorithm, which estimates utility values based on responses to the SF-12, which was administered at baseline and 6, 12, 18 and 24 months post randomisation and at the time of a sore throat episode. The CBA estimated the incremental net benefit, comparing costs and benefits in monetary terms. Participants’ WTP values, estimated from the contingent valuation study, were multiplied by participants’ self-reported number of sore throat days to estimate the reduction in patient benefits in monetary terms; from this costs were subtracted to give the net benefit. Qualitative process evaluation Qualitative and cognitive interviews were carried out by researchers from Newcastle University for the feasibility study, pilot and main trial. Interviews were held with adult patients with acute tonsillitis who had been referred to ENT outpatient clinics for recurrent sore throats, ENT staff who were working at a National Trial of Tonsillectomy IN Adults (NATTINA) trial site and GPs. These interviews addressed the acceptability of the trial/treatments, unforeseen consequences from the perspective of participants and how patient experience may shape future research. Statistical analysis The primary statistical analysis was carried out on an intention-to-treat (ITT) basis, retaining patients in their randomised arms and including protocol violator and ineligible patients. Patients randomised to conservative management were asked to commit to ‘deferred surgery’. We anticipated that a number of patients would take the opportunity to switch to surgery. We also undertook sensitivity analyses, including a per-treatment (as treated) and a per-protocol analysis. The cumulative total number of sore throat days reported on a patient level was provided separately for each randomised arm. Negative binomial regression was used to compare these, adjusting for stratification variables (baseline severity as a fixed effect and site as a random effect). The summary comparative statistic reported is the incident rate ratio (IRR). The analysis took account of incomplete weekly returns by use of an exposure variable included in the model. The analysis of secondary outcomes followed a broadly similar strategy to the primary outcome. Analyses were adjusted for baseline severity and site, and repeated measures were analysed using random-effects models with appropriate error structure. Results Primary outcome The participants in this trial reported a median of 27 [interquartile range (IQR) 12–52] sore throats over the full 24 months of follow-up. Fewer sore throats were reported in the tonsillectomy arm (median 23, IQR 11–46) than in the conservative management arm (median 30, IQR 14–65). When the primary outcome (total sore throats) was compared between the two randomised arms on an ITT basis, a reduction in sore throats was seen in the tonsillectomy arm. The tonsillectomy arm had 0.53 [IRR, 95% confidence interval (CI) 0.43 to 0.65] times the total sore throat days over the 24-month period than those in the conservative management arm. Sensitivity analyses on the ITT population confirmed this result. The analysis of the per-protocol population of 224 participants had, on average, a greater reduction in the number of sore throats, with patients in the tonsillectomy arm having 0.42 (IRR 95% CI 0.31 to 0.55) times the total score throats compared with the conservative management arm. Around 25% of participants did not receive the treatment that they were randomised to, which meant that some opted not to receive a tonsillectomy and some opted to cross to tonsillectomy. There is evidence to suggest that those with larger numbers of sore throats following randomisation were more likely to either opt for or remain in the tonsillectomy arm. Conversely, those with slightly smaller numbers of sore throats following randomisation were more likely to remain in conservative management or opt out of the tonsillectomy arm. Despite these crossovers, the ITT, per-protocol and per-treated analyses all confirmed that there was a significant reduction in total sore throats for those randomised to tonsillectomy. Secondary outcome measures The benefits of tonsillectomy were also seen in the secondary outcome measures. Tonsillectomy Outcome Inventory-14 (TOI-14) scores improved in both arms, but show a greater improvement in the tonsillectomy arm than the conservative management arm, where at 12 months the difference between the mean scores was –13.17 units (95% CI –17.41 to –8.92 units), indicating a reduction in symptoms. The SF-12 MCS and SF-12 PCS also show significant and beneficial differences in favour of the tonsillectomy arm over time [SF-12 MCS scores 3.71 units higher (95% CI 2.10 to 5.47) and SF-12 PCS 2.77 units higher (95% CI 0.30 to 5.23) in the tonsillectomy arm than the conservative management arm]. Adverse events There were 52 episodes of post-operative haemorrhage reported in 231 participants undergoing tonsillectomy (22.5%). Of these episodes, 35 were reported as SAEs: 8 as mild events, 22 as moderate events and 5 as severe events. No deaths were reported. Seventeen episodes were recorded as AEs, for which patients did not attend hospital. All episodes of bleeding were managed conservatively with no returns to theatre. Economic evaluation On average, tonsillectomy was more costly and more effective than conservative management. In the CEA, the incremental cost to avoid a sore throat episode was £24 per sore throat day. From the contingent valuation, the mean WTP to avoid a sore throat day was £43 (95% CI £2 to £100). In the CUA, tonsillectomy had an 87% probability of being considered cost-effective at a £5000 threshold for an additional QALY; this increased to 100% as the threshold values for an additional QALY increased. In the CBA, tonsillectomy had a 69% probability of having a higher net benefit than conservative management. Qualitative study Trial processes were deemed as acceptable, with only a few sites experiencing barriers to treatment. The use of technology to collect data was particularly well received. However, there were some challenges with recruitment, particularly for staff who lacked equipoise. ENT staff alluded to having to negotiate surgery dates with patients, which, at times, meant that they had to deviate from trial protocols. Some patients did not fully understand the process of randomisation. Patients who had received surgery were unanimous in reporting to be happy to have undertaken this, despite the challenging recovery period. Limitations There was some evidence that those with the most severe extent of disease were reluctant to enter the study (around 5 points higher scores overall on the TOI-14). Some symptoms may not be a result of tonsillitis. Not all patients were offered, or chose, to watch the trial recruitment video. The ITT analysis is likely to offer a conservative underestimate of the true impact of tonsillectomy in reducing sore throat days, as a result of patients crossing over to receive tonsillectomy. A challenge of the economic evaluation was the progressive loss of data over the 24-month follow-up. Conclusions Tonsillectomy in adults is a clinically effective intervention. It was more costly but had a high probability of being considered cost-effective over the range of analyses conducted. Participants with recurrent tonsillitis, who met current UK NHS guidelines to undergo tonsillectomy, suffered significantly fewer sore throat days over 24 months than similar participants treated conservatively. How should health services react? Pre-NATTINA, UK guidelines were a translation of level 1 evidence in children, applied to adults. Access to tonsillectomy in the UK was governed by application of national guidance, which is predicated on a qualifying number of episodes of tonsillitis. NATTINA participants in the tonsillectomy arm reported, on average, fewer healthcare contacts, fewer sore throat days and higher QALYs than those in the conservative management arm. Within the UK, tonsillectomy is listed as a ‘procedure of limited clinical value’ (The Royal College of Surgeons of England. Procedures of Limited Clinical Value: Royal College of Surgeons Briefing. London: The Royal College of Surgeons of England; 2011). To the best of our knowledge, NATTINA is the first definitive trial to demonstrate that tonsillectomy performed according to the current UK national guidelines is effective for patients, and the probability of it being considered cost-effective is high. Guideline reassessment, in particular how guidelines translate into healthcare commissioning, is called for. How should practitioners and patients respond to these findings? We have identified communication issues at the primary–secondary care interface in our qualitative work. There is, therefore, a need to convert the findings of NATTINA into a practical decision support tool for patients and surgeons. Implications for research (in priority order) The top research priority to emerge from NATTINA is to determine the optimum timing of tonsillectomy in adults with recurrent acute tonsillitis. Work is required also to optimise metrics for disease burden severity, and to exploit the novel real-time data collection methods elaborated in NATTINA. There is also a need to better understand optimum treatment strategies, including oral steroids, for tonsillitis in primary care. Trial registration This trial is registered as ISRCTN55284102. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 12/146/06) and is published in full in Health Technology Assessment; Vol. 27, No. 31. See the NIHR Funding and Awards website for further award information.

Background: Daily, low-dose antibiotic prophylaxis is the current standard care for women with recurrent urinary tract infection. Emerging antimicrobial resistance is a global health concern, prompting research interest in non-antibiotic agents such as methenamine hippurate, but comparative data on their efficacy and safety are lacking. Objective: To assess the clinical effectiveness and cost-effectiveness of methenamine hippurate (Hiprex®; Mylan NV, Canonsburg, PA, USA) compared with current standard care (antibiotic prophylaxis) for recurrent urinary tract infection prevention in adult women. Design: Multicentre, pragmatic, open-label, randomised, non-inferiority trial of 12 months’ treatment with the allocated intervention, including an early, embedded qualitative study and a 6-month post-treatment observation phase. The predefined non-inferiority margin was one urinary tract infection per person-year. Setting: Eight UK NHS secondary care sites. Participants: A total of 240 adult women with recurrent urinary tract infection requiring preventative treatment participated in the trial. Interventions: A central randomisation system allocated participants 1 : 1 to the experimental (methenamine hippurate: 1 g twice daily) or control (once-daily low-dose antibiotics: 50/100 mg of nitrofurantoin, 100 mg of trimethoprim or 250 mg of cefalexin) arm. Crossover between treatment arms was permitted. Main outcome measures: The primary clinical outcome was incidence of symptomatic antibiotic-treated urinary tract infection during the 12-month treatment period. Cost-effectiveness was assessed by incremental cost per quality-adjusted life-year gained, extrapolated over the patient’s expected lifetime using a Markov cohort model. Secondary outcomes included post-treatment urinary tract infections, total antibiotic use, microbiologically proven urinary tract infections, antimicrobial resistance, bacteriuria, hospitalisations and treatment satisfaction. Results: Primary modified intention-to-treat analysis comprised 205 (85%) randomised participants [102/120 (85%) participants in the antibiotics arm and 103/120 (86%) participants in the methenamine hippurate arm] with at least 6 months’ data available. During treatment, the incidence rate of symptomatic, antibiotic-treated urinary tract infections decreased substantially in both arms to 1.38 episodes per person-year (95% confidence interval 1.05 to 1.72 episodes per person-year) for methenamine hippurate and 0.89 episodes per person year (95% confidence interval 0.65 to 1.12 episodes per person-year) for antibiotics (absolute difference 0.49; 90% confidence interval 0.15 to 0.84). This absolute difference did not exceed the predefined, strict, non-inferiority limit of one urinary tract infection per person-year. On average, methenamine hippurate was less costly and more effective than antibiotics in terms of quality-adjusted life-years gained; however, this finding was not consistent over the longer term. The urinary tract infection incidence rate 6 months after treatment completion was 1.72 episodes per year in the methenamine hippurate arm and 1.19 in the antibiotics arm. During treatment, 52% of urine samples taken during symptomatic urinary tract infections were microbiologically confirmed and higher proportions of participants taking daily antibiotics (46/64; 72%) demonstrated antibiotic resistance in Escherichia coli cultured from perineal swabs than participants in the methenamine hippurate arm (39/70; 56%) (p-value = 0.05). Urine cultures revealed that during treatment higher proportions of participants and samples from the antibiotic arm grew E. coli resistant to trimethoprim/co-trimoxazole and cephalosporins, respectively. Conversely, post treatment, higher proportions of participants in the methenamine hippurate arm (9/45; 20%) demonstrated multidrug resistance in E. coli isolated from perineal swabs than participants in the antibiotic arm (2/39; 5%) (p = 0.06). All other secondary outcomes and adverse events were similar in both arms. Limitations: This trial could not define whether or not one particular antibiotic was more beneficial, and progressive data loss hampered economic evaluation. Conclusions: This large, randomised, pragmatic trial in a routine NHS setting has clearly shown that methenamine hippurate is not inferior to current standard care (daily low-dose antibiotics) in preventing recurrent urinary tract infections in women. The results suggest that antimicrobial resistance is proportionally higher in women taking prophylactic antibiotics. Recommendations for research: Future research should include evaluation of other non-antibiotic preventative treatments in well-defined homogeneous patient groups, preferably with the comparator of daily antibiotics. Trial registration: This trial is registered as ISRCTN70219762 and EudraCT 2015-003487-36. Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 23. See the NIHR Journals Library website for further project information.

Abstract Background A three-arm parallel group, randomised controlled trial set in general dental practices in England, Scotland, and Wales was undertaken to evaluate three strategies to manage dental caries in primary teeth. Children, with at least one primary molar with caries into dentine, were randomised to receive Conventional with best practice prevention (C + P), Biological with best practice prevention (B + P), or best practice Prevention Alone (PA). Methods Data on costs were collected via case report forms completed by clinical staff at every visit. The co-primary outcomes were incidence of, and number of episodes of, dental pain and/or infection avoided. The three strategies were ranked in order of mean cost and a more costly strategy was compared with a less costly strategy in terms of incremental cost-effectiveness. Costs and outcomes were discounted at 3.5%. Results A total of 1144 children were randomised with data on 1058 children (C + P n = 352, B + P n = 352, PA n = 354) used in the analysis. On average, it costs £230 to manage dental caries in primary teeth over a period of up to 36 months. Managing children in PA was, on average, £19 (97.5% CI: -£18 to £55) less costly than managing those in B + P. In terms of effectiveness, on average, there were fewer incidences of, (− 0.06; 97.5% CI: − 0.14 to 0.02) and fewer episodes of dental pain and/or infection (− 0.14; 97.5% CI: − 0.29 to 0.71) in B + P compared to PA. C + P was unlikely to be considered cost-effective, as it was more costly and less effective than B + P. Conclusions The mean cost of a child avoiding any dental pain and/or infection (incidence) was £330 and the mean cost per episode of dental pain and/or infection avoided was £130. At these thresholds B + P has the highest probability of being considered cost-effective. Over the willingness to pay thresholds considered, the probability of B + P being considered cost-effective never exceeded 75%. Trial registration The trial was prospectively registered with the ISRCTN (reference number ISRCTN77044005) on the 26th January 2009 and East of Scotland Research Ethics Committee provided ethical approved (REC reference: 12/ES/0047).

Introduction ACOSOG-Z0011(Z11) trial showed that axillary node clearance (ANC) may be omitted in women with ≤2 positive nodes undergoing breast conserving surgery (BCS) and whole breast radiotherapy (RT). A confirmatory study is needed to clarify the role of axillary treatment in women with ≤2 macrometastases undergoing BCS and groups that were not included in Z11 for example, mastectomy and those with microscopic extranodal invasion. The primary objective of POsitive Sentinel NOde: adjuvant therapy alone versus adjuvant therapy plus Clearance or axillary radiotherapy (POSNOC) is to evaluate whether for women with breast cancer and 1 or 2 macrometastases, adjuvant therapy alone is non-inferior to adjuvant therapy plus axillary treatment, in terms of 5-year axillary recurrence.Methods and analysis POSNOC is a pragmatic, multicentre, non-inferiority, international trial with participants randomised in a 1:1 ratio. Women are eligible if they have T1/T2, unifocal or multifocal invasive breast cancer, and 1 or 2 macrometastases at sentinel node biopsy, with or without extranodal extension. In the intervention group women receive adjuvant therapy alone, in the standard care group they receive ANC or axillary RT. In both groups women receive adjuvant therapy, according to local guidelines. This includes systemic therapy and, if indicated, RT to breast or chest wall. The UK Radiotherapy Trials Quality Assurance Group manages the in-built radiotherapy quality assurance programme. Primary endpoint is 5-year axillary recurrence. Secondary outcomes are arm morbidity assessed by Lymphoedema and Breast Cancer Questionnaire and QuickDASH questionnaires; quality of life and anxiety as assessed with FACT B+4 and State/Trait Anxiety Inventory questionnaires, respectively; other oncological outcomes; economic evaluation using EQ-5D-5L. Target sample size is 1900. Primary analysis is per protocol. Recruitment started on 1 August 2014 and as of 9 June 2021, 1866 participants have been randomised.Ethics and dissemination Protocol was approved by the National Research Ethics Service Committee East Midlands—Nottingham 2 (REC reference: 13/EM/0459). Results will be submitted for publication in peer-reviewed journals.Trial registration number ISRCTN54765244; NCT0240168Cite Now

Background: Patients diagnosed with advanced primary open-angle glaucoma are at a high risk of lifetime blindness. Uncertainty exists about whether primary medical management (glaucoma eye drops) or primary surgical treatment (augmented trabeculectomy) provide the best and safest patient outcomes. Objectives: To compare primary medical management with primary surgical treatment (augmented trabeculectomy) in patients with primary open-angle glaucoma presenting with advanced disease in terms of health-related quality of life, clinical effectiveness, safety and cost-effectiveness. Design: This was a two-arm, parallel, multicentre, pragmatic randomised controlled trial. Setting: Secondary care eye services. Participants: Adult patients presenting with advanced primary open-angle glaucoma in at least one eye, as defined by the Hodapp–Parrish–Anderson classification of severe glaucoma. Intervention: Primary medical treatment – escalating medical management with glaucoma eye drops. Primary trabeculectomy treatment – trabeculectomy augmented with mitomycin C. Main outcome measures: The primary outcome was health-related quality of life measured with the Visual Function Questionnaire-25 at 2 years post randomisation. Secondary outcomes were mean intraocular pressure; EQ-5D-5L; Health Utilities Index 3; Glaucoma Utility Index; cost and cost-effectiveness; generic, vision-specific and disease-specific health-related quality of life; clinical effectiveness; and safety. Results: A total of 453 participants were recruited. The mean age of the participants was 67 years (standard deviation 12 years) in the trabeculectomy arm and 68 years (standard deviation 12 years) in the medical management arm. Over 65% of participants were male and more than 80% were white. At 24 months, the mean difference in Visual Function Questionnaire-25 score was 1.06 (95% confidence interval –1.32 to 3.43; p = 0.383). There was no evidence of a difference between arms in the EQ-5D-5L score, the Health Utilities Index or the Glaucoma Utility Index. At 24 months, the mean intraocular pressure was 12.40 mmHg in the trabeculectomy arm and 15.07 mmHg in the medical management arm (mean difference –2.75 mmHg, 95% confidence interval –3.84 to –1.66 mmHg; p

Abstract Background Falls in people with dementia can result in a number of physical and psychosocial consequences. However, there is limited evidence to inform how best to deliver services to people with dementia following a fall. The aim of the DIFRID study was to determine the feasibility of developing and implementing a new intervention to improve outcomes for people with dementia with fall-related injuries; this encompasses both short-term recovery and reducing the likelihood of future falls. This paper details the development of the DIFRID intervention. Methods The intervention was designed using an integrated, mixed-methods approach. This involved a realist synthesis of the literature and qualitative data gathered through interviews and focus groups with health and social care professionals (n = 81). An effectiveness review and further interviews and observation were also conducted and are reported elsewhere. A modified Delphi panel approach with 24 experts was then used to establish a consensus on how the findings should translate into a new intervention. After feedback from key stakeholders (n = 15) on the proposed model, the intervention was manualised and training developed. Results We identified key components of a new intervention covering three broad areas: • Ensuring that the circumstances of rehabilitation are optimised for people with dementia • Compensating for the reduced ability of people with dementia to self-manage • Equipping the workforce with the necessary skills and information to care for this patient group Consensus was achieved on 54 of 69 statements over two rounds of the Delphi surveys. The statements were used to model the intervention and finalise the accompanying manual and protocol for a feasibility study. Stakeholder feedback was generally positive and the majority of suggested intervention components were approved. The proposed outcome was a 12-week complex multidisciplinary intervention primarily based at the patient’s home. Conclusions A new intervention has been developed to improve outcomes for people with dementia following a fall requiring healthcare attention. The feasibility of this intervention is currently being tested. Trial registration ISRCTN41760734 (16/11/2015).

Background: Historically, lack of evidence for effective management of decay in primary teeth has caused uncertainty, but there is emerging evidence to support alternative strategies to conventional fillings, which are minimally invasive and prevention orientated. Objectives: The objectives were (1) to assess the clinical effectiveness and cost-effectiveness of three strategies for managing caries in primary teeth and (2) to assess quality of life, dental anxiety, the acceptability and experiences of children, parents and dental professionals, and caries development and/or progression. Design: This was a multicentre, three-arm parallel-group, participant-randomised controlled trial. Allocation concealment was achieved by use of a centralised web-based randomisation facility hosted by Newcastle Clinical Trials Unit. Setting: This trial was set in primary dental care in Scotland, England and Wales. Participants: Participants were NHS patients aged 3–7 years who were at a high risk of tooth decay and had at least one primary molar tooth with decay into dentine, but no pain/sepsis. Interventions: Three interventions were employed: (1) conventional with best-practice prevention (local anaesthetic, carious tissue removal, filling placement), (2) biological with best-practice prevention (sealing-in decay, selective carious tissue removal and fissure sealants) and (3) best-practice prevention alone (dietary and toothbrushing advice, topical fluoride and fissure sealing of permanent teeth). Main outcome measures: The clinical effectiveness outcomes were the proportion of children with at least one episode (incidence) and the number of episodes, for each child, of dental pain or dental sepsis or both over the follow-up period. The cost-effectiveness outcomes were the cost per incidence of, and cost per episode of, dental pain and/or dental sepsis avoided over the follow-up period. Results: A total of 72 dental practices were recruited and 1144 participants were randomised (conventional arm, n = 386; biological arm, n = 381; prevention alone arm, n = 377). Of these, 1058 were included in an intention-to-treat analysis (conventional arm, n = 352; biological arm, n = 352; prevention alone arm, n = 354). The median follow-up time was 33.8 months (interquartile range 23.8–36.7 months). The proportion of children with at least one episode of pain or sepsis or both was 42% (conventional arm), 40% (biological arm) and 45% (prevention alone arm). There was no evidence of a difference in incidence or episodes of pain/sepsis between arms. When comparing the biological arm with the conventional arm, the risk difference was –0.02 (97.5% confidence interval –0.10 to 0.06), which indicates, on average, a 2% reduced risk of dental pain and/or dental sepsis in the biological arm compared with the conventional arm. Comparing the prevention alone arm with the conventional arm, the risk difference was 0.04 (97.5% confidence interval –0.04 to 0.12), which indicates, on average, a 4% increased risk of dental pain and/or dental sepsis in the prevention alone arm compared with the conventional arm. Compared with the conventional arm, there was no evidence of a difference in episodes of pain/sepsis among children in the biological arm (incident rate ratio 0.95, 97.5% confidence interval 0.75 to 1.21, which indicates that there were slightly fewer episodes, on average, in the biological arm than the conventional arm) or in the prevention alone arm (incident rate ratio 1.18, 97.5% confidence interval 0.94 to 1.48, which indicates that there were slightly more episodes in the prevention alone arm than the conventional arm). Over the willingness-to-pay values considered, the probability of the biological treatment approach being considered cost-effective was approximately no higher than 60% to avoid an incidence of dental pain and/or dental sepsis and no higher than 70% to avoid an episode of pain/sepsis. Conclusions: There was no evidence of an overall difference between the three treatment approaches for experience of, or number of episodes of, dental pain or dental sepsis or both over the follow-up period. Future work: Recommendations for future work include exploring barriers to the use of conventional techniques for carious lesion detection and diagnosis (e.g. radiographs) and developing and evaluating suitable techniques and strategies for use in young children in primary care. Trial registration: Current Controlled Trials ISRCTN77044005. Funding: This 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. 24, No. 1. See the NIHR Journals Library website for further project information.

Abstract Background INVESTIGATE-I (INVasive Evaluation before Surgical Treatment of Incontinence Gives Added Therapeutic Effect?) was a mixed methods study to assess the feasibility of a future randomised controlled trial of invasive urodynamic testing (IUT) prior to surgery for stress urinary incontinence (SUI) in women. Here we report one of the study’s five components, with the specific objectives of (i) exploring the cost-effectiveness of IUT compared with clinical assessment plus non-invasive tests (henceforth described as ‘IUT’ and ‘no IUT’ respectively) in women with SUI or stress-predominant mixed urinary incontinence (MUI) prior to surgery, and (ii) determining the expected net gain (ENG) from additional research. Methods Study participants were women with SUI or stress-predominant MUI who had failed to respond to conservative treatments recruited from seven UK urogynaecology and female urology units. They were randomised to receive either ‘IUT’ or ‘no IUT’ before undergoing further treatment. Data from 218 women were used in the economic analysis. Cost utility, net benefit and value of information (VoI) analyses were performed within a randomised controlled pilot trial. Costs and quality-adjusted life years (QALYs) were estimated over 6 months to determine the incremental cost per QALY of ‘IUT’ compared to ‘no IUT’. Net monetary benefit informed the VoI analysis. The VoI estimated the ENG and optimal sample size for a future definitive trial. Results At 6 months, the mean difference in total average cost was £138 (p = 0.071) in favour of ‘IUT’; there was no difference in QALYs estimated from the SF-12 (difference 0.004; p = 0.425) and EQ-5D-3L (difference − 0.004; p = 0.725); therefore, the probability of IUT being cost-effective remains uncertain. The estimated ENG was positive for further research to address this uncertainty with an optimal sample size of 404 women. Conclusions This is the largest economic evaluation of IUT. On average, up to 6 months after treatment, ‘IUT’ may be cost-saving compared to ‘no IUT’ because of the reduction in surgery following invasive investigation. However, uncertainty remains over the probability of ‘IUT’ being considered cost-effective, especially in the longer term. The VoI analysis indicated that further research would be of value. Trial registration ISRCTN. ISRCTN71327395. Registered 7 June 2010.

Background: Fall-related injuries are a significant cause of morbidity and mortality in people with dementia. There is presently little evidence to guide the management of such injuries, and yet there are potentially substantial benefits to be gained if the outcomes of these injuries could be improved. This study aimed to design an appropriate new health-care intervention for people with dementia following a fall and to assess the feasibility of its delivery in the UK NHS. Objectives: To determine whether or not it is possible to design an intervention to improve outcomes of falls in dementia, to investigate the feasibility and acceptability of the DIFRID (Developing an Intervention for Fall related Injuries in Dementia) intervention and to investigate the feasibility of a future randomised controlled trial and the data collection tools needed to evaluate both the effectiveness and the cost-effectiveness of the DIFRID intervention. Design: This was a mixed-methods feasibility study. A systematic review (using Cochrane methodology) and realist review [using Realist And Meta-narrative Evidence Syntheses: Evolving Standards (RAMESES) methodology] explored the existing evidence base and developed programme theories. Searches were carried out in November 2015 (updated in January 2018) for effectiveness studies and in August 2016 for economic studies. A prospective observational study identified service use via participant diary completion. Qualitative methods (semistructured interviews, focus groups and observation) were used to explore current practice, stakeholder perspectives of the health and social care needs of people with dementia following a fall, ideas for intervention and barriers to and facilitators of change. Each of the resulting data sets informed intervention development via Delphi consensus methods. Finally, a single-arm feasibility study with embedded process evaluation was conducted. Setting: This study was set in the community. Participants: The participants were (1) people with dementia presenting with falls necessitating health-care attention in each setting (primary care, the community and secondary care) at three sites and their carers, (2) professionals delivering the intervention, who were responsible for training and supervision and who were members of the intervention team, (3) professionals responsible for approaching and recruiting participants and (4) carers of participants with dementia. Interventions: This was a complex multidisciplinary therapy intervention. Physiotherapists, occupational therapists and support workers delivered up to 22 sessions of tailored activities in the home or local area of the person with dementia over a period of 12 weeks. Main outcome measures: (1) Assessment of feasibility of study procedures; (2) assessment of the acceptability, feasibility and fidelity of intervention components; and (3) assessment of the suitability and acceptability of outcome measures for people with dementia and their carers (number of falls, quality of life, fear of falling, activities of daily living, goal-setting, health-care utilisation and carer burden). Results: A multidisciplinary intervention delivered in the homes of people with dementia was designed based on qualitative work, realist review and recommendations of the consensus panel. The intervention was delivered to 11 people with dementia. The study suggested that the intervention is both feasible and acceptable to stakeholders. A number of modifications were recommended to address some of the issues arising during feasibility testing. The measurement of outcome measures was successful. Conclusions: The study has highlighted the feasibility of delivering a creative, tailored, individual approach to intervention for people with dementia following a fall. Although the intervention required greater investment of time than usual practice, many staff valued the opportunity to work more closely with people with dementia and their carers. We conclude that further research is now needed to refine this intervention in the context of a pilot randomised controlled trial. Trial registration: Current Controlled Trials ISRCTN41760734 and PROSPERO CRD42016029565. Funding: This 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. 23, No. 59. See the NIHR Journals Library website for further project information.

Background: Alcoholic hepatitis (AH) is a distinct presentation of alcoholic liver disease arising in patients who have been drinking to excess for prolonged periods, which is characterised by jaundice and liver failure. Severe disease is associated with high short-term mortality. Prednisolone and pentoxifylline (PTX) are recommended in guidelines for treatment of severe AH, but trials supporting their use have given heterogeneous results and controversy persists about their benefit. Objectives: The aim of the clinical effectiveness and cost-effectiveness of STeroids Or Pentoxifylline for Alcoholic Hepatitis trial was to resolve the clinical dilemma on the use of prednisolone or PTX. Design: The trial was a randomised, double-blind, 2 × 2 factorial, multicentre design. Setting: Sixty-five gastroenterology and hepatology inpatient units across the UK. Participants: Patients with a clinical diagnosis of AH who had a Maddrey’s discriminant function value of ≥ 32 were randomised into four arms: A, placebo/placebo; B, placebo/prednisolone; C, PTX/placebo; and D, PTX/prednisolone. Of the 5234 patients screened for the trial, 1103 were randomised and after withdrawals, 1053 were available for primary end-point analysis. Interventions: Those allocated to prednisolone were given 40 mg daily for 28 days and those allocated to PTX were given 400 mg three times per day for 28 days. Outcomes: The primary outcome measure was mortality at 28 days. Secondary outcome measures included mortality or liver transplant at 90 days and at 1 year. Rates of recidivism among survivors and the impact of recidivism on mortality were assessed. Results: At 28 days, in arm A, 45 of 269 (16.7%) patients died; in arm B, 38 of 266 (14.3%) died; in arm C, 50 of 258 (19.4%) died; and in arm D, 35 of 260 (13.5%) died. For PTX, the odds ratio for 28-day mortality was 1.07 [95% confidence interval (CI) 0.77 to 1.40; p = 0.686)] and for prednisolone the odds ratio was 0.72 (95% CI 0.52 to 1.01; p = 0.056). In the logistic regression analysis, accounting for indices of disease severity and prognosis, the odds ratio for 28-day mortality in the prednisolone-treated group was 0.61 (95% CI 0.41 to 0.91; p = 0.015). At 90 days and 1 year there were no significant differences in mortality rates between the treatment groups. Serious infections occurred in 13% of patients treated with prednisolone compared with 7% of controls (p = 0.002). At the 90-day follow-up, 45% of patients reported being completely abstinent, 9% reported drinking within safety limits and 33% had an unknown level of alcohol consumption. At 1 year, 37% of patients reported being completely abstinent, 10% reported drinking within safety limits and 39% had an unknown level of alcohol consumption. Only 22% of patients had attended alcohol rehabilitation treatment at 90 days and 1 year. Conclusions: We conclude that prednisolone reduces the risk of mortality at 28 days, but this benefit is not sustained beyond 28 days. PTX had no impact on survival. Future research should focus on interventions to promote abstinence and on treatments that suppress the hepatic inflammation without increasing susceptibility to infection. Trial registration: This trial is registered as EudraCT 2009-013897-42 and Current Controlled Trials ISRCTN88782125. Funding: This 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. 19, No. 102. See the NIHR Journals Library website for further project information. The NIHR Clinical Research Network provided research nurse support and the Imperial College Biomedical Research Centre also provided funding.

Background: The position of invasive urodynamic testing in the diagnostic pathway for urinary incontinence (UI) is unclear. Systematic reviews have called for further trials evaluating clinical utility, although a preliminary feasibility study was considered appropriate. Objectives: To inform the decision whether or not to proceed to a definitive randomised trial of invasive urodynamic testing compared with clinical assessment with non-invasive tests, prior to surgery in women with stress UI (SUI) or stress predominant mixed UI (MUI). Design: A mixed-methods study comprising a pragmatic multicentre randomised pilot trial; economic evaluation; survey of clinicians’ views about invasive urodynamic testing; qualitative interviews with clinicians and trial participants. Setting: Urogynaecology, female urology and general gynaecology units in Newcastle, Leicester, Swansea, Sheffield, Northumberland, Gateshead and South Tees. Participants: Trial recruits were women with SUI or stress predominant MUI who were considering surgery after unsuccessful conservative treatment. Relevant clinicians completed two online surveys. Subsets of survey respondents and trial participants took part in separate qualitative interview studies. Interventions: Pilot trial participants were randomised to undergo clinical assessment with non-invasive tests (control arm); or assessment as controls, plus invasive urodynamic testing (intervention arm). Main outcome measures: Confirmation that units can identify and recruit eligible women; acceptability of investigation strategies and data collection tools; acquisition of outcome data to determine the sample size for a definitive trial. The proposed primary outcome for the definitive trial was International Consultation on Incontinence Modular Questionnaire (ICIQ) Female Lower Urinary Tract Symptoms (ICIQ-FLUTS) (total score) 6 months after surgery or the start of non-surgical treatment; secondary outcomes included: ICIQ-FLUTS (subscales); ICIQ Urinary Incontinence Short Form; ICIQ Lower Urinary Tract Symptoms Quality of Life; Urogenital Distress Inventory; EuroQol-5D; costs, quality-adjusted life-years (QALYs) and incremental cost per QALY, Short Form 12; 3-day bladder diary. Results: Of 284 eligible women, 222 (78%) were recruited; 165/219 (75%) returned questionnaires at baseline and 125/200 (63%) who were sent questionnaires at follow-up. There were few missing data items in returned questionnaires, with individual outcome scales calculable for 81%–94%. Most women underwent surgery; management plans were changed in 19 (19%) participants following invasive urodynamic testing. Participant Costs Questionnaires were returned by 53% 6 months after treatment; complete data to undertake cost–utility analysis were available in 27% (intervention) and 47% (control). While insufficient to recommend changes in practice, the results suggest further research would be valuable. All clinicians responding to the survey had access to invasive urodynamic testing, and most saw it as essential prior to surgery in women with SUI with or without other symptoms; nevertheless, 70% considered the research question underlying INVESTIGATE important and most were willing to randomise patients in a definitive trial. Participants interviewed were positive about the trial and associated documentation; the desire of some women to avoid invasive urodynamic testing contrasted with opinions expressed by clinicians through both survey and interview responses. Conclusions: All elements of a definitive trial and economic evaluation were rehearsed; several areas for protocol modification were identified. Such a trial would require to 400–900 participants, depending on the difference in primary outcome sought. Future work: A definitive trial of invasive urodynamic testing versus clinical assessment prior to surgery for SUI or stress predominant MUI should be undertaken. Trial registration: Current Controlled Trials ISRCTN71327395. Funding: The National Institute for Health Research Health Technology Assessment programme.