Victoria Bell

Background: Asthma affects over 1 million children across the UK, and preventative treatment is guided subjectively by patient symptoms. Spirometry is an objective test of lung function and can be used in children to guide treatment. However, current guidelines do not indicate how asthma treatment should change in the context of changing spirometry results. This study will evaluate how spirometry can be used to guide asthma treatment and reduce the risk for asthma attacks in children. Methods: This is a multi-centre, randomised controlled trial. Children aged 6–15 years, who have a diagnosis of asthma and have had an exacerbation requiring oral or intravenous corticosteroids in the previous 12 months, will be eligible. Exclusion criteria include being unable to provide spirometry measurement at baseline assessment, having another chronic respiratory condition and being currently treated with maintenance oral steroids or biologicals. Participants will be recruited in both primary and secondary care settings and will be randomised to either receive asthma treatment guided by spirometry plus symptoms (intervention group) or asthma treatment guided by symptoms only (standard care group). Within the spirometry group, treatment recommendations will be dependent on changes in spirometry measurements. Participants will attend assessments 3, 6, 9 and 12 months post-randomisation, where treatment recommendations will be made. The primary outcome is the number of asthma attacks per participant requiring treatment with 1–7 days of oral or intravenous corticosteroid over 12 months, as recorded by the participant or parent. Secondary outcomes include time to first attack, any asthma attack, adverse events, dose of inhaled corticosteroids, asthma control and quality of life. Adherence to inhaled corticosteroid treatment is measured by an electronic logging device. Discussion: This study will evaluate whether asthma treatment guided by spirometry will reduce future asthma attacks in children. Our findings may be relevant to national and international asthma guidelines. Trial registration: ISRCTN, ISRCTN31849868. Registered on 01.07.2022. Prospectively registered.

Background: Renal tract stone disease is common. The three intervention options are shockwave lithotripsy, flexible ureteroscopic stone treatment and keyhole surgery. Objectives: To determine which of shockwave lithotripsy, flexible ureteroscopic stone treatment and keyhole surgery offer the best outcomes in terms of health and quality of life, clinical effectiveness and cost-effectiveness for people with lower pole kidney stones. Design: The PUrE study comprised two pragmatic multicentre, open-label, superiority randomised controlled trials: RCT1 for lower pole stones ≤ 10 mm and RCT2 for lower pole stones > 10 and ≤ 25 mm. Setting: National Health Service Urology departments. Participants: Adults presenting with lower pole renal stones, able to undergo any of the treatments and complete trial procedures. Intervention: Eligible participants were randomised in RCT1 to flexible ureteroscopic stone treatment or shockwave lithotripsy; and in RCT2 to flexible ureteroscopic stone treatment or keyhole surgery. Main outcome measures: The primary outcome measure was health status ‘area under the curve’, measured weekly to 12 weeks post intervention with the EuroQol-5 Dimensions, five-level version. The primary economic outcome was the incremental cost per quality-adjusted life-year gained at 12 months from randomisation. Results: RCT1: A total of 461 participants were randomised: 231 to flexible ureteroscopic stone treatment; and 230 to shockwave lithotripsy. RCT2: A total of 159 participants were randomised: 73 to flexible ureteroscopic stone treatment; and 86 to keyhole surgery. Primary outcome: RCT1: The mean health status area under the curve was 0.807 (standard deviation 0.205) in the flexible ureteroscopic stone treatment group (n = 164) and 0.826 (standard deviation 0.207) in the shockwave lithotripsy group (n = 188). The between-group difference, 0.024 (95% confidence interval −0.004 to 0.053), was a small difference in favour of flexible ureteroscopic stone treatment after correcting for a baseline imbalance. Complete stone clearance was higher with flexible ureteroscopic stone treatment (72%) than shockwave lithotripsy (36%). RCT2: The mean health status area under the curve was 0.794 (standard deviation 0.198) in the flexible ureteroscopic stone treatment group (n = 57) and 0.818 (standard deviation 0.217) in the keyhole surgery group (n = 63). The between-group difference, −0.07 (95% confidence interval −0.11 to −0.02), was a borderline meaningful difference favouring keyhole surgery. Complete stone clearance was higher with keyhole surgery (71%) than flexible ureteroscopic stone treatment (48%). Economic evaluation: RCT1: Flexible ureteroscopic stone treatment is more costly (£1138; 95% confidence interval £646 to £1631) and produces 0.017 (95% confidence interval −0.008 to 0.043) additional quality-adjusted life-years; with an incremental cost-effectiveness ratio of £65,163 per quality-adjusted life-year gained. Shockwave lithotripsy has a 99.9% chance of being cost-effective at a £20,000 threshold value. RCT2: Flexible ureteroscopic stone treatment is more costly (£733; 95% confidence interval −£508 to £1973) and produces fewer quality-adjusted life-years (−0.001; 95% confidence interval −0.044 to 0.042). Keyhole surgery has an 87% chance of being cost-effective at a £20,000 threshold value. Limitations: Blinding of participants and healthcare providers was not possible. There were differential waiting times between interventions in RCT1; however, adjusting for this gave similar treatment effect estimates. Conclusions: The PUrE study found in RCT1 that shockwave lithotripsy was more cost-effective than flexible ureteroscopic stone treatment, with no meaningful difference in patient health status even though complete stone-free rates were higher with flexible ureteroscopic stone treatment. In RCT2, keyhole surgery was more cost-effective than flexible ureteroscopic stone treatment on a micro-costing basis, which better reflects treatment cost differences to the NHS. Keyhole surgery was marginally beneficial for health status with higher complete stone-free rates. Future work: What effect will suction devices, improvements in laser technology, and intraoperative pressure monitoring have on postoperative pain, quality of life, stone-free rates, complications, and costs of flexible ureteroscopic stone treatment? What effect does miniaturisation of keyhole surgery have on postoperative pain, length of stay, complications, stone-free rates and costs? Trial registration: This trial is registered as ISRCTN98970319. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 13/152/02) and is published in full in Health Technology Assessment; Vol. 29, No. 40. See the NIHR Funding and Awards website for further award information.

Background: Overactive bladder is a common problem affecting the United Kingdom adult female population. Symptoms include urinary urgency, with or without urgency incontinence, increased daytime urinary frequency and nocturia. Initial conservative treatments for overactive bladder are unsuccessful in 25–40% of women (refractory overactive bladder). Before considering invasive treatments, such as botulinum toxin injection-A or sacral neuromodulation, guidelines recommend urodynamics to confirm diagnosis of detrusor overactivity. However, the clinical and cost effectiveness of urodynamics has never been robustly assessed. Objectives: To compare the clinical and cost effectiveness of urodynamics plus comprehensive clinical assessment versus comprehensive clinical assessment only in the management of refractory overactive bladder in women. Design: Parallel-group, multicentre, superiority, open-label, randomised controlled trial. Allocation by remote web-based randomisation (1 : 1 ratio). The cost-effectiveness analysis took the National Health Service perspective with a model-based lifetime time horizon, as informed by a within-trial analysis. Setting: Sixty-three United Kingdom secondary and tertiary hospitals. Participants: Women aged ≥ 18 years with refractory overactive bladder or urgency-predominant mixed urinary incontinence who had failed conservative management and pharmacological treatment and were being considered for invasive treatment. Women were excluded if any of the following criteria were met: predominant stress urinary incontinence; previous urodynamics in last 12 months; current pelvic malignancy or clinically significant pelvic mass; bladder pain syndrome; neurogenic bladder; urogenital fistulae; previous treatment with botulinum toxin injection-A or sacral neuromodulation for urinary incontinence; previous pelvic radiotherapy; prolapse beyond introitus; pregnant or planning pregnancy; recurrent urinary tract infection where a significant pathology has not been excluded; and inability to give an informed consent. Interventions: Urodynamics plus comprehensive clinical assessment (urodynamics arm) versus comprehensive clinical assessment only. Main outcome measures: Participant-reported success at the last follow-up time point as measured by the Patient Global Impression of Improvement. Primary economic outcome was incremental cost per quality-adjusted life-year gained as modelled over the lifetime of participants. Results: A total of 1099 participants were included: 550 randomised to the urodynamics arm and 549 to the comprehensive clinical assessment only arm. At the final follow-up time point, participant-reported success rates of ‘very much improved’ and ‘much improved’ were not superior in the urodynamics arm (117 participants; 23.6%) compared to the comprehensive clinical assessment only arm (114 participants; 22.7%) [adjusted odds ratio 1.12 (95% confidence interval 0.73 to 1.74); p = 0.601]. Serious adverse events were low and similar between groups. Based on the estimated incremental costs and quality-adjusted life-years of urodynamics (£463 and 0.011, respectively), the incremental cost-effectiveness ratio was £42,643 per quality-adjusted life-year gained. The cost-effectiveness acceptability curve shows that urodynamics has a 34% probability of being cost-effective at a willingness-to-pay threshold of £20,000 per quality-adjusted life-year gained. This probability reduced further when the results were extrapolated over the patient’s lifetime. Limitations include: only short-term outcomes were available, and as most participants underwent botulinum toxin injection-A treatment, pre-planned secondary analyses for some outcomes such as sacral neuromodulation were not possible. Conclusion: Participant-reported success in the urodynamics arm was not superior to the comprehensive clinical assessment only arm at 15-months follow-up. Urodynamics is not cost-effective at a threshold of £20,000 per quality-adjusted life-year gained. Longer-term follow-up is required to explore need for further interventions and treatments and their effect on the clinical and cost-effectiveness analyses. Trial registration: This trial is registered as ISRCTN63268739. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 15/150/05) and is published in full in Health Technology Assessment Vol. 29, No. 27. See the NIHR Funding and Awards website for further award information.

Objective To assess the clinical and cost effectiveness of conservative management compared with laparoscopic cholecystectomy for the prevention of symptoms and complications in adults with uncomplicated symptomatic gallstone disease. Design Parallel group, pragmatic randomised, superiority trial. Setting 20 secondary care centres in the UK. Participants 434 adults (>18 years) with uncomplicated symptomatic gallstone disease referred to secondary care, assessed for eligibility between August 2016 and November 2019, and randomly assigned (1:1) to receive conservative management or laparoscopic cholecystectomy. Interventions Conservative management or surgical removal of the gallbladder. Main outcome measures The primary patient outcome was quality of life, measured by area under the curve, over 18 months using the short form 36 (SF-36) bodily pain domain, with higher scores (range 0-100) indicating better quality of life. Other outcomes included costs to the NHS, quality adjusted life years (QALYs), and incremental cost effectiveness ratio. Results Of 2667 patients assessed for eligibility, 434 were randomised: 217 to the conservative management group and 217 to the laparoscopic cholecystectomy group. By 18 months, 54 (25%) participants in the conservative management arm and 146 (67%) in the cholecystectomy arm had received surgery. The mean SF-36 norm based bodily pain score was 49.4 (standard deviation 11.7) in the conservative management arm and 50.4 (11.6) in the cholecystectomy arm. The SF-36 bodily pain area under the curve up to 18 months did not differ (mean difference 0.0, 95% confidence interval −1.7 to 1.7; P=1.00). Conservative management was less costly (mean difference −£1033, (−$1334; −€1205), 95% credible interval −£1413 to −£632) and QALYs did not differ (mean difference −0.019, 95% credible interval −0.06 to 0.02). Conclusions In the short term (≤18 months), laparoscopic surgery is no more effective than conservative management for adults with uncomplicated symptomatic gallstone disease, and as such conservative management should be considered as an alternative to surgery. From an NHS perspective, conservative management may be cost effective for uncomplicated symptomatic gallstone disease. As costs, complications, and benefits will continue to be incurred in both groups beyond 18 months, future research should focus on longer term follow-up to establish effectiveness and lifetime cost effectiveness and to identify the cohort of patients who should be routinely offered surgery. Trial registration ISRCTN registry ISRCTN55215960.

Background: The role of fractional exhaled nitric oxide in guiding asthma treatment in children is uncertain.Objective: To compare treatment guided by both fractional exhaled nitric oxide and symptoms (intervention) with treatment guided by symptoms alone (standard care) in children with asthma who are at risk of an asthma exacerbation, in terms of the number of asthma exacerbations over 12 months.Design: This was a pragmatic, multicentre, randomised controlled trial with embedded cost-effectiveness and qualitative process evaluations. Randomisation (1 : 1) was carried out using a remote web-based system and was minimised on recruitment centre, age, sex and British Thoracic Society treatment step. Clinical teams and participants were not blind to treatment allocation.Setting: The trial took place in 35 hospitals and seven primary care practices in the UK.Participants: Children aged 6–15 years with a diagnosis of asthma who were currently prescribed inhaled corticosteroids and who had one or more parent-/patient-reported asthma exacerbation treated with oral corticosteroids in the 12 months prior to recruitment.Interventions: Asthma treatment guided by symptoms alone (standard care) and asthma treatment guided by symptoms plus fractional exhaled nitric oxide (intervention). Treatment recommendations in both groups were protocolised within a web-based algorithm, incorporating inhaled corticosteroid adherence (objectively measured using an electronic logging device) and current treatment.Main outcome measures: The primary outcome measure was asthma exacerbations treated with oral corticosteroids in the year post randomisation. Secondary outcomes included time to first exacerbation, number of exacerbations, lung function, fractional exhaled nitric oxide, daily dose of inhaled corticosteroid, asthma control and quality of life.Results: In total, 509 eligible participants were recruited and the primary outcome was available for 506 participants. The primary outcome occurred in 123 out of 255 (48.2%) participants in the intervention group and 129 out of 251 (51.4%) participants in the standard-care group (adjusted odds ratio 0.88, 95% confidence interval 0.61 to 1.27). There was algorithm non-compliance on 21% of assessments. Per-protocol and complier-average causal effect analysis did not change the interpretation. This non-statistically significant estimate was consistent across predefined subgroups. There were no differences between the groups in secondary outcomes. There were no serious adverse events or deaths. No meaningful differences in health service costs, direct patient costs or indirect costs to society were identified between the groups. The economic evaluation does not provide evidence to support the cost-effectiveness of the intervention. In the qualitative process evaluation, 15 trial staff and six families were interviewed. Overall, their experiences were positive. The intervention was broadly acceptable, with caveats around clinicians using the algorithm recommendation as a guide and wariness around extreme step ups/downs in treatment in the light of contextual factors not being taken into account by the algorithm.Limitations: Potential limitations included the choice of cut-off point to define uncontrolled asthma and the change in fractional exhaled nitric oxide to trigger a change in treatment. Furthermore, the treatment decisions in the two groups may not have been sufficiently different to create a difference in outcomes.Conclusions: The RAACENO (Reducing Asthma Attacks in Children using Exhaled Nitric Oxide) trial findings do not support the routine use of fractional exhaled nitric oxide measurements as part of asthma management in a secondary care setting. The potential for other objective markers to guide asthma management in children needs to be evaluated.Trial registration: This trial was registered as ISRCTN67875351.Funding: This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a MRC and National Institute for Health and Care Research (NIHR) partnership. This will be published in full inEfficacy and Mechanism Evaluation; Vol. 9, No. 4. See the NIHR Journals Library website for further project information.