Health Technology Assessment Programme Research Articles

HTA and National Immunisation Program: an overview of competent bodies and of the impact of HTA on the decision-making process

Abstract Issue/problem The WHO has recommended for many years to adopt transparent and standardized methods to decide upon the introduction of vaccines at national level. For this purpose, the Global Vaccine Action Plan has envisaged the establishment of National Immunization Technical Advisory Groups (NITAGs) to issue independent advice relied on the assessment of vaccines efficacy and safety and health technology assessment (HTA). Description of the problem So far, 172 countries worldwide have a NITAG. Despite the growth in the number of NITAGs worldwide and their strengthening following process indicators identified by the WHO, the way how NITAGs issue recommendations and how they are considered in the development of vaccine policy still represent a matter to the attention of the scientific and policy community. Results The evidence shows that assessment frameworks vary across countries. Furthermore, the legal basis and the authority, namely binding or advisory, recognised to them could influence the way how NITAGs work and impact on vaccine policy. Eventually, the final decision is also led by other aspects, including financial and contextual factors that are less standardizable but should be always taken into consideration in health policy. In fact, the final decision on the inclusion of a vaccination into the national immunization program is made by the Ministry of Health also based on the evaluation of HTA bodies working in the country. Lessons Considering the central role of NITAGs in vaccine policy, some efforts should be done in order to make NITAGs more authoritative and collaborative. This could help, from one side, to make the relationship between final decision and NITAGs recommendations clearer and, on other one, to make it possible to have shared and timely evaluations. In this respect, Joint Clinical Assessment envisaged by the new EU regulation on HTA could prepare the way for a more transparent and timely vaccine policy at European level.

Percutaneous Revascularization for Ischemic Left Ventricular Dysfunction

BackgroundWhether revascularization by percutaneous coronary intervention (PCI) can improve event-free survival and left ventricular function in patients with severe ischemic left ventricular systolic dysfunction, as compared with optimal medical therapy (i.e., individually adjusted pharmacologic and device therapy for heart failure) alone, is unknown.MethodsWe randomly assigned patients with a left ventricular ejection fraction of 35% or less, extensive coronary artery disease amenable to PCI, and demonstrable myocardial viability to a strategy of either PCI plus optimal medical therapy (PCI group) or optimal medical therapy alone (optimal-medical-therapy group). The primary composite outcome was death from any cause or hospitalization for heart failure. Major secondary outcomes were left ventricular ejection fraction at 6 and 12 months and quality-of-life scores.ResultsA total of 700 patients underwent randomization — 347 were assigned to the PCI group and 353 to the optimal-medical-therapy group. Over a median of 41 months, a primary-outcome event occurred in 129 patients (37.2%) in the PCI group and in 134 patients (38.0%) in the optimal-medical-therapy group (hazard ratio, 0.99; 95% confidence interval [CI], 0.78 to 1.27; P=0.96). The left ventricular ejection fraction was similar in the two groups at 6 months (mean difference, −1.6 percentage points; 95% CI, −3.7 to 0.5) and at 12 months (mean difference, 0.9 percentage points; 95% CI, −1.7 to 3.4). Quality-of-life scores at 6 and 12 months appeared to favor the PCI group, but the difference had diminished at 24 months.ConclusionsAmong patients with severe ischemic left ventricular systolic dysfunction who received optimal medical therapy, revascularization by PCI did not result in a lower incidence of death from any cause or hospitalization for heart failure. (Funded by the National Institute for Health and Care Research Health Technology Assessment Program; REVIVED-BCIS2 ClinicalTrials.gov number, NCT01920048.)

Cost-effectiveness of statin therapy in categories of patients in the UK

Abstract Background Cardiovascular disease (CVD) mortality has declined steadily over the last few decades across Europe and North America. Purpose To provide contemporary estimates of long-term effectiveness and cost-effectiveness of statin therapy in different categories of patients in UK. Methods The CTT-UKB micro-simulation model, developed using the Cholesterol Treatment Trialists' Collaboration data (CTT: 118,000 participants; 5 years follow-up), and calibrated in the UK Biobank cohort (UKB: 502,000 participants; 9 years follow-up). The model integrates parametric risk equations for incident myocardial infarction, stroke, coronary revascularization, diabetes, cancer and vascular and nonvascular death, and projects annually these endpoints and survival using patient characteristics at entry. UKB data and linked primary and hospital care data informed healthcare costs in the model (2020 UK£); 2021 UK NHS Drug Tariff informed statin costs (atorvastatin 40mg at £1.22 and 80mg at £1.68 per 28 tablets); and Health Survey for England data informed health-related quality of life in the model. Previous CTT meta-analysis, atorvastatin dose-response randomized trials, and further meta-analyses of statin trials and cohort studies informed effects of 40mg/80mg atorvastatin therapy daily on rates of incident myocardial infarction, stroke, coronary revascularization, vascular death, diabetes, myopathy and rhabdomyolysis. The model was used to project gains in quality-adjusted life years (QALYs) and additional cost per QALY with lifetime use of atorvastatin 40mg or 80mg daily in categories of UKB participants by sex, age at statin initiation (40–49; 50–59 and 60–70 years), and 10-year CVD risk (QRISK3 risk (%): <5; 5–10, 10–15, 15–20, ≥20). Further scenarios explored effects of 5-year delay of statin initiation in people under 45 years of age or stopping statin therapy at 80 years of age. Results Across men and women in categories by age and CVD risk, lifetime use of atorvastatin 40mg daily was associated with increases in survival by 0.44–1.69 years (0.28–1.02 QALYs), and atorvastatin 80mg daily with increases in survival of 0.45–1.87 years (0.32–1.13 QALYs; Figure 1) with gains larger among participants at higher CVD risk. Both atorvastatin 40mg and 80mg doses were in the range of cost-effective treatments with incremental cost per QALY gained with atorvastatin 40mg daily versus no statin therapy below £7200/QALY and with atorvastatin 80mg vs 40mg daily below £16000/QALY (Figure 2) across all patient categories studied. Compared to lifetime statin therapy, stopping therapy at 80 years of age substantially reduced benefits and was not cost-effective in any patient category studied. Similarly, compared to immediate initiation, 5-year delay of statin therapy in 40–45 years old patients was not a cost-effective. Conclusions In the UK, statin therapy remains highly cost-effective across men and women 40–70 years old, including those at 10-year CVD risk <5%. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): UK National Institute for Health Research (NIHR) Health Technology Assessment (HTA) Programme, UK National Institute for Health Research (NIHR) Health Technology Assessment (HTA) Programme, UK Medical Research Council (MRC), British Heart Foundation

Benefit accrual with cardiovascular disease prevention and effects of discontinuation: a modelling study

Abstract Background Statin therapy reduces rates of heart attacks and strokes and improves survival in people at increased cardiovascular disease (CVD) risk. However, there is some uncertainty when to start and how long to persist with statin therapy so as to optimise benefits. Purpose To project the accrual of benefit with statin therapy in population groups by age at therapy initiation using a newly developed micro-simulation model. Methods Participants without previous CVD (N=44,412) and with previous CVD (N=13,061) at entry were randomly selected from the UK Biobank cohort, ensuring sufficient representation in respective categories by age, LDL cholesterol, diabetes and 10-year CVD risk categories (QRISK3 score, for those without previous CVD only). The CTT-UKB model, a CVD micro-simulation model [1], was used to predict subsequent survival and quality-adjusted life years (QALYs) of the participants using their characteristics at entry. Treatment with atorvastatin 40mg daily was used as an example to illustrate the effect of the therapy compared to no such therapy. Scenarios include: (1) lifelong preventive therapy, (2) preventive therapy stopped at 80 years of age, and (3) delayed initiation of preventive therapy by 5 years in participants under 45 years of age. Results Statin treatment benefits, measured in QALYs gained, accrue over lifetime. The majority of benefits accrue later in life. Men accumulate larger benefits and earlier than women (Figure 1A). The pattern of benefits accrual is similar for participants with and without previous CVD (data not shown). The higher the participants' CVD risk, the larger and earlier the benefits, with younger participants accruing larger benefits (Figure 1B). Compared with lifelong prevention, stopping treatment at 80 years of age leads to large reductions in overall benefits, especially in women and those at lower CVD risk. For example, compared to lifelong therapy, people without previous CVD who initiate therapy in their 50s, would lose 47% of QALYs benefit (if men), 66% (if women), 73% (if with CVD risk <5%), and 35% (if with CVD risk ≥20%), respectively, if they stop treatment when they reach 80 years of age. Five-year delay of statin therapy initiation in people under 45 years of age reduces their benefits by about 4% on average, though the loss is somewhat larger in people at higher CVD risk (Figure 2). Conclusion Benefits from lifelong cardiovascular prevention accrue over peoples' lifespan with large share of benefits accruing at older age. Stopping treatment earlier substantially reduces benefits. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): UK NationalInstitute for Health Research (NIHR) Health Technology Assessment (HTA) Programme, UK Medical Research Council (MRC), and British Heart Foundation

Impact of cardiovascular events on primary and hospital care costs: findings from UK Biobank study

Abstract Background Need for primary and secondary healthcare increases following cardiovascular disease (CVD) events but there is no data on comparative increases in costs. Purpose To estimate annual primary care and hospital inpatient costs associated with key CVD and other adverse events using the UK Biobank (UKB) individual participant data. Methods UKB participants with linked primary care data (192,983 participants) or hospital inpatient episodes data (all 501,807 participants) contributed data to this study. The three categories of primary care services (patient consultations, diagnostic and monitoring tests, prescription medications), and hospital episodes were costed (2020 UK£) using the NHS England reference costs. Annual primary care costs and, separately, annual hospital inpatient costs were modelled as functions of participant characteristics at entry (socio-demographic, clinical, prior diseases) and time-updated first occurrences of myocardial infarction, stroke, coronary revascularization, incident cancer, incident diabetes, vascular death and non-vascular death during follow-up (p-value <0.01 in stepwise covariate selection). One-part generalized linear regression model (GLM) with Poisson distribution and identity link function was used for primary care costs, and two-part model was used for inpatient costs (part 1: logistic regression models probability of incurring costs; part 2: GLM with Poisson distribution and identity link function models costs conditional on incurring any). Separate models were fitted among participants with and without previous CVD at entry into UKB. Results Most adverse events were associated with excess primary care and hospital inpatient costs. Compared to people without previous CVD, people with previous CVD had on average larger excess primary care and hospital inpatient costs in years with myocardial infarction, stroke and vascular death; but similar excess costs in years with other events. Among both people without and with previous CVD, the excess annual primary care costs were less than 7% of the excess annual hospital inpatient costs for vascular events (Table). However, following diabetes diagnosis the excess annual primary care costs were higher than the excess annual hospital inpatient costs (Table). Conclusions These excess primary and hospital care costs associated with CVD events could inform assessments of interventions and policies to reduce CVD risks in UK. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): UK National Institute for Health Research (NIHR) Health Technology Assessment (HTA) Programme, UK Medical Research Council (MRC), British Heart Foundation

Patient preferences and current practice for adults with steroid-resistant ulcerative colitis: POPSTER mixed-methods study.

Corticosteroids are a mainstay of the treatment of moderately severe relapses of ulcerative colitis, yet almost 50% of patients do not respond fully to these and risk prolonged steroid use and side effects. There is a lack of clarity about the definitions of steroid resistance, the optimum choice of treatment, and patient and health-care professional treatment preferences. The overall aim of this research was to understand how steroid-resistant ulcerative colitis is managed in adult secondary care and how current practice compares with patient and health-care professional preferences. A mixed-methods study, including an online survey, qualitative interviews and discrete choice experiments. NHS inflammatory bowel disease services in the UK. Adults with ulcerative colitis and health-care professionals treating inflammatory bowel disease. We carried out a survey of health-care professionals (n = 168), qualitative interviews with health-care professionals (n = 20) and patients (n = 33), discrete choice experiments with health-care professionals (n = 116) and patients (n = 115), and a multistakeholder workshop (n = 9). The interviews with and survey of health-care professionals showed that most health-care professionals define steroid resistance as an incomplete response to 40 mg per day of prednisolone after 2 weeks. The survey also found that anti-tumour necrosis factor drugs (particularly infliximab) are the most frequently offered drugs across most steroid-resistant (and steroid-dependent) patient scenarios, but they are less frequently offered to thiopurine-naive patients. Patient interviews identified several factors influencing their treatment choices, including effectiveness of treatment, recommendations from health-care professionals, route of administration and side effects. Over time, depending on the severity and duration of symptoms and, crucially, as medical treatment options become exhausted, patients are willing to try alternative treatments and, eventually, to undergo surgery. The discrete choice experiments found that the probability of remission and of side effects strongly influences the treatment choices of both patients and health-care professionals. Patients are less likely to choose a treatment that takes longer to improve symptoms. Health-care professionals are willing to make difficult compromises by tolerating greater safety risks in exchange for therapeutic benefits. The treatments ranked most positively by patients were infliximab and tofacitinib (each preferred by 38% of patients), and the predicted probability of uptake by health-care professionals was greatest for infliximab (62%). The survey and the discrete choice experiments with patients and health-care professionals are limited by their relatively small sample sizes. The qualitative studies are subject to selection bias. The timing of the different substudies, both before and during the COVID-19 pandemic, is a potential limitation. We have identified factors influencing treatment decisions for steroid-resistant ulcerative colitis and the characteristics to consider when choosing treatments to evaluate in future randomised controlled trials. The findings may be used to improve discussions between patients and health-care professionals when they review treatment options for steroid-resistant ulcerative colitis. This research highlights the need for consensus work to establish an agreed definition of steroid resistance in ulcerative colitis and a greater understanding of the optimal use of tofacitinib and surgery for this patient group. A randomised controlled trial comparing infliximab with tofacitinib is also recommended. 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. 41. See the NIHR Journals Library website for further project information.

Monofilament suture versus braided suture thread to improve pregnancy outcomes after vaginal cervical cerclage (C-STICH): a pragmatic randomised, controlled, phase 3, superiority trial

Miscarriage in the second trimester and preterm birth are significant global problems. Vaginal cervical cerclage is performed to prevent pregnancy loss and preterm birth. We aimed to determine the effectiveness of a monofilament suture thread compared with braided suture thread on pregnancy loss rates in women undergoing a cervical cerclage. C-STICH was a pragmatic, randomised, controlled, superiority trial done at 75 obstetric units in the UK. Women with a singleton pregnancy who received a vaginal cervical cerclage due to a history of pregnancy loss or premature birth, or if indicated by ultrasound, were centrally randomised (1:1) using minimisation to receive a monofilament suture or braided suture thread for their cervical cerclage. Women and outcome assessors were masked to allocation as far as possible. The primary outcome was pregnancy loss, defined as miscarriage, stillbirth, or neonatal death in the first week of life, analysed in the intention-to-treat population (ie, all women who were randomly assigned). Safety was also assessed in the intention-to-treat population. The trial was registered with ISRCTN, ISRCTN15373349. Between Aug 21, 2015, and Jan 28, 2021, 2049 women were randomly assigned to receive a monofilament suture (n=1025) or braided suture (n=1024). The primary outcome was ascertained in 1003 women in the monofilament suture group and 993 women in the braided suture group. Pregnancy loss occurred in 80 (8·0%) of 1003 women in the monofilament suture group and 75 (7·6%) of 993 women in the braided suture group (adjusted risk ratio 1·05 [95% CI 0·79 to 1·40]; adjusted risk difference 0·002 [95% CI -0·02 to 0·03]). Monofilament suture did not reduce rate of pregnancy loss when compared with a braided suture. Clinicians should use the results of this trial to facilitate discussions around the choice of suture thread to optimise outcomes. National Institute of Health Research Health Technology Assessment Programme.

A Randomized Trial of PHOTOdynamic Surgery in Non–Muscle-Invasive Bladder Cancer

BackgroundRecurrence of non–muscle-invasive bladder cancer (NMIBC) is common after transurethral resection of bladder tumor (TURBT). Photodynamic diagnosis (PDD) provides better diagnostic accuracy and more complete tumor resection and may reduce recurrence. However, there is limited evidence on the longer-term clinical effectiveness and cost-effectiveness of PDD-guided resection.MethodsIn this pragmatic, open-label, parallel-group randomized trial conducted in 22 U.K. National Health Service hospitals, we recruited participants with a suspected first diagnosis of NMIBC at intermediate or high risk for recurrence on the basis of routine visual assessment before being listed for TURBT. Participants were assigned (1:1) to PDD-guided TURBT or to standard white light (WL)–guided TURBT. The primary clinical outcome was time to recurrence at 3 years of follow-up, analyzed by modified intention to treat.ResultsA total of 538 participants were enrolled (269 in each group), and 112 participants without histologic confirmation of NMIBC or who had had cystectomy were excluded. After 44 months’ median follow-up, 86 of 209 in the PDD group and 84 of 217 in the WL group had recurrences. The hazard ratio for recurrence was 0.94 (95% confidence interval [CI], 0.69 to 1.28; P=0.70). Three-year recurrence-free rates were 57.8% (95% CI, 50.7 to 64.2) and 61.6% (95% CI, 54.7 to 67.8) in the PDD and WL groups, respectively, with an absolute difference of −3.8 percentage points (95% CI, −13.37 to 5.59) favoring PDD. Adverse events occurred in less than 2% of participants, and rates were similar in both groups, as was health-related quality of life. PDD-guided TURBT was £876 (95% CI, −766 to 2518; P=0.591) more costly than WL-guided TURBT over a 3-year follow-up, with no evidence of a difference in quality-adjusted life years (−0.007; 95% CI, −0.133 to 0.119; P=0.444).ConclusionsPDD-guided TURBT did not reduce recurrence rates, nor was it cost-effective compared with WL at 3 years. (Funded by the National Institute for Health and Care Research Health Technology Assessment program; ISRCTN number, ISRCTN84013636.)

Plasma exchange and glucocorticoids to delay death or end-stage renal disease in anti-neutrophil cytoplasm antibody-associated vasculitis: PEXIVAS non-inferiority factorial RCT.

Plasma exchange and glucocorticoids to delay death or end-stage renal disease in anti-neutrophil cytoplasm antibody-associated vasculitis: PEXIVAS non-inferiority factorial RCT.

Managing the introduction of genomic applications into the National Health Service: A special challenge for health technology assessment in Italy.

In recent years, the rapid proliferation of genomic tests for use in clinical practice has prompted healthcare systems to use a health technology assessment (HTA) approach to distinguish valuable from unwarranted applications. In this study, we narratively review the Italian HTA mechanisms for medical devices (MDs), both at the national and regional levels, and discuss the opportunity and benefits of extending them to genomic technologies, for which a dedicated assessment path was advocated by the National Plan for Public Health Genomics in 2017. We found that the National Health Technology Assessment Program for MDs, completed in 2019, had developed a structured pathway for the HTA of MDs; it established a hub-and-spoke structure, run by a governmental institution, and put in place transparent methodological procedures to cover all four HTA phases (i.e., proposal and prioritization, assessment, appraisal, and dissemination). However, several factors have hindered its adoption, and the regions are at different stages of its implementation. For these reasons, efforts should be made to ensure its effective deployment, both at national and regional levels. In addition, we argue that to harmonize the institutional roles and methodological procedures adopted, the time has come to concentrate resources on a single pathway for the assessment of all technologies that include both MDs and genomic applications.

Early computed tomography coronary angiography in adults presenting with suspected acute coronary syndrome: the RAPID-CTCA RCT.

Acute coronary syndrome is a common medical emergency. The optimal strategy to investigate patients who are at intermediate risk of acute coronary syndrome has not been fully determined. To investigate the role of early computed tomography coronary angiography in the investigation and treatment of adults presenting with suspected acute coronary syndrome. A prospective, multicentre, open, parallel-group randomised controlled trial with blinded end-point adjudication. Thirty-seven hospitals in the UK. Adults (aged ≥ 18 years) presenting to the emergency department, acute medicine services or cardiology department with suspected or provisionally diagnosed acute coronary syndrome and at least one of the following: (1) a prior history of coronary artery disease, (2) a cardiac troponin level > 99th centile and (3) an abnormal 12-lead electrocardiogram. Early computed tomography coronary angiography in addition to standard care was compared with standard care alone. Participants were followed up for 1 year. One-year all-cause death or subsequent type 1 (spontaneous) or type 4b (stent thrombosis) myocardial infarction, measured as the time to such event adjudicated by two cardiologists blinded to the computerised tomography coronary angiography ( CTCA ) arm. Cost-effectiveness was estimated as the lifetime incremental cost per quality-adjusted life-year gained. Between 23 March 2015 and 27 June 2019, 1748 participants [mean age 62 years (standard deviation 13 years), 64% male, mean Global Registry Of Acute Coronary Events score 115 (standard deviation 35)] were randomised to receive early computed tomography coronary angiography (n = 877) or standard care alone (n = 871). The primary end point occurred in 51 (5.8%) participants randomised to receive computed tomography coronary angiography and 53 (6.1%) participants randomised to receive standard care (adjusted hazard ratio 0.91, 95% confidence interval 0.62 to 1.35; p = 0.65). Computed tomography coronary angiography was associated with a reduced use of invasive coronary angiography (adjusted hazard ratio 0.81, 95% confidence interval 0.72 to 0.92; p = 0.001) but no change in coronary revascularisation (adjusted hazard ratio 1.03, 95% confidence interval 0.87 to 1.21; p = 0.76), acute coronary syndrome therapies (adjusted odds ratio 1.06, 95% confidence interval 0.85 to 1.32; p = 0.63) or preventative therapies on discharge (adjusted odds ratio 1.07, 95% confidence interval 0.87 to 1.32; p = 0.52). Early computed tomography coronary angiography was associated with longer hospitalisations (median increase 0.21 days, 95% confidence interval 0.05 to 0.40 days) and higher mean total health-care costs over 1 year (£561 more per patient) than standard care. The principal limitation of the trial was the slower than anticipated recruitment, leading to a revised sample size, and the requirement to compromise and accept a larger relative effect size estimate for the trial intervention. The potential role of computed tomography coronary angiography in selected patients with a low probability of obstructive coronary artery disease (intermediate or mildly elevated level of troponin) or who have limited access to invasive cardiac catheterisation facilities needs further prospective evaluation. In patients with suspected or provisionally diagnosed acute coronary syndrome, computed tomography coronary angiography did not alter overall coronary therapeutic interventions or 1-year clinical outcomes, but it did increase the length of hospital stay and health-care costs. These findings do not support the routine use of early computed tomography coronary angiography in intermediate-risk patients with acute chest pain. This trial is registered as ISRCTN19102565 and Clinical Trials NCT02284191. 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. 37. See the NIHR Journals Library website for further project information.

A modified video-feedback intervention for carers of foster children aged 6 years and under with reactive attachment disorder: a feasibility study and pilot RCT.

Looked-after children are at risk of suboptimal attachment patterns and reactive attachment disorder. However, access to interventions varies widely and there are no evidence-based interventions for this disorder. (1) To adapt an existing video-feedback intervention to meet the specific needs of foster children in the UK with reactive attachment symptoms, (2) to conduct a case series to road-test the treatment manual and study procedures, (3) to conduct a scoping study of the key hurdles in a pilot trial and (4) to conduct a pilot randomised controlled trial of the adapted intervention to determine the feasibility of a future full-scale trial. This was a mixed-methods study. The adapted treatment manual was developed with expert input and tested on a small case series. Qualitative interviews with key stakeholders were used in the scoping study in preparation for the trial and later with foster carers who received the new intervention. The final stage was a feasibility and pilot randomised controlled trial of the new intervention, compared with usual care. Researchers assessing the outcomes were blinded to group assignment. The study was set in outpatient child and adolescent mental health services and partner social services departments. Sites included urban and rural/semirural areas. Participants were foster carers with children aged ≤ 6 years presenting with difficulties in the domain of reactive attachment disorder. Key stakeholders included children's services managers and mental health service practitioners in the scoping study. Foster carers who received the modified intervention participated in qualitative interviews. The video-feedback intervention to promote positive parenting and sensitive discipline is an extensively evaluated and effective treatment approach. This intervention was modified (based on the adapted version for foster care in the Netherlands) to suit the needs of young children with reactive attachment symptoms in foster care in the UK and was delivered to improve the sensitive responding of foster carers, foster carer-child relationships and child outcomes. The modified intervention was delivered in-home by trained mental health professionals over a period of 4-6 months. The main outcome was reactive attachment symptom scores on the Disturbances of Attachment Interview. A series of minor changes to the intervention programme were introduced, which focused on improving its suitability for the UK foster care context. Challenges in recruitment meant that, despite numerous modifications to the protocol and the inclusion of additional sites, only 30 families (target, n = 40) were recruited to the randomised controlled trial (15 allocated to each group). However, most other trial parameters were deemed feasible and acceptable, particularly the high levels of data and treatment completeness. All randomised families were available for baseline analyses, but two in the treatment arm were not available for post-treatment analyses. The revised intervention was positively received by practitioners and foster carers. Only three-quarters of the target sample size was recruited. Furthermore, the sites' own exclusion of potential participants and the low return rates of screening questionnaires raise the possibility of non-randomness of non-responses. A larger-scale trial may be feasible, but only if recruitment barriers can be overcome. Dedicated resources to support recruitment within local authorities and wider inclusion criteria are recommended. Central resourcing of intervention capacity to supplement NHS staff is also recommended. This trial is registered as ISRCTN18374094. 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. 35. See the NIHR Journals Library website for further project information.

Hughes abdominal closure versus standard mass closure to reduce incisional hernias following surgery for colorectal cancer: the HART RCT.

Incisional hernias can cause chronic pain and complications and affect quality of life. Surgical repair requires health-care resources and has a significant associated failure rate. A prospective, multicentre, single-blinded randomised controlled trial was conducted to investigate the clinical effectiveness and cost-effectiveness of the Hughes abdominal closure method compared with standard mass closure following surgery for colorectal cancer. The study randomised, in a 1 : 1 ratio, 802 adult patients (aged ≥ 18 years) undergoing surgical resection for colorectal cancer from 28 surgical departments in UK centres. Hughes abdominal closure or standard mass closure. The primary outcome was the incidence of incisional hernias at 1 year, as assessed by clinical examination. Within-trial cost-effectiveness and cost-utility analyses over 1 year were conducted from an NHS and a social care perspective. A key secondary outcome was quality of life, and other outcomes included the incidence of incisional hernias as detected by computed tomography scanning. The incidence of incisional hernia at 1-year clinical examination was 50 (14.8%) in the Hughes abdominal closure arm compared with 57 (17.1%) in the standard mass closure arm (odds ratio 0.84, 95% confidence interval 0.55 to 1.27; p = 0.4). In year 2, the incidence of incisional hernia was 78 (28.7%) in the Hughes abdominal closure arm compared with 84 (31.8%) in the standard mass closure arm (odds ratio 0.86, 95% confidence interval 0.59 to 1.25; p = 0.43). Computed tomography scanning identified a total of 301 incisional hernias across both arms, compared with 100 identified by clinical examination at the 1-year follow-up. Computed tomography scanning missed 16 incisional hernias that were picked up by clinical examination. Hughes abdominal closure was found to be less cost-effective than standard mass closure. The mean incremental cost for patients undergoing Hughes abdominal closure was £616.45 (95% confidence interval -£699.56 to £1932.47; p = 0.3580). Quality of life did not differ significantly between the study arms at any time point. As this was a pragmatic trial, the control arm allowed surgeon discretion in the approach to standard mass closure, introducing variability in the techniques and equipment used. Intraoperative randomisation may result in a loss of equipoise for some surgeons. Follow-up was limited to 2 years, which may not have been enough time to see a difference in the primary outcome. Hughes abdominal closure did not significantly reduce the incidence of incisional hernias detected by clinical examination and was less cost-effective at 1 year than standard mass closure in colorectal cancer patients. Computed tomography scanning may be more effective at identifying incisional hernias than clinical examination, but the clinical benefit of this needs further research. An extended follow-up using routinely collected NHS data sets aims to report on incisional hernia rates at 2-5 years post surgery to investigate any potential mortality benefit of the closure methods. Furthermore, the proportion of incisional hernias identified by a computed tomography scan (at 1 and 2 years post surgery), but not during clinical examination (occult hernias), proceeding to surgical repair within 3-5 years after the initial operation will be explored. This trial is registered as ISRCTN25616490. 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. 34. See the NIHR Journals Library website for further project information.

Comparison of amitriptyline supplemented with pregabalin, pregabalin supplemented with amitriptyline, and duloxetine supplemented with pregabalin for the treatment of diabetic peripheral neuropathic pain (OPTION-DM): a multicentre, double-blind, randomised crossover trial

SummaryBackgroundDiabetic peripheral neuropathic pain (DPNP) is common and often distressing. Most guidelines recommend amitriptyline, duloxetine, pregabalin, or gabapentin as initial analgesic treatment for DPNP, but there is little comparative evidence on which one is best or whether they should be combined. We aimed to assess the efficacy and tolerability of different combinations of first-line drugs for treatment of DPNP.MethodsOPTION-DM was a multicentre, randomised, double-blind, crossover trial in patients with DPNP with mean daily pain numerical rating scale (NRS) of 4 or higher (scale is 0–10) from 13 UK centres. Participants were randomly assigned (1:1:1:1:1:1), with a predetermined randomisation schedule stratified by site using permuted blocks of size six or 12, to receive one of six ordered sequences of the three treatment pathways: amitriptyline supplemented with pregabalin (A-P), pregabalin supplemented with amitriptyline (P-A), and duloxetine supplemented with pregabalin (D-P), each pathway lasting 16 weeks. Monotherapy was given for 6 weeks and was supplemented with the combination medication if there was suboptimal pain relief (NRS >3), reflecting current clinical practice. Both treatments were titrated towards maximum tolerated dose (75 mg per day for amitriptyline, 120 mg per day for duloxetine, and 600 mg per day for pregabalin). The primary outcome was the difference in 7-day average daily pain during the final week of each pathway. This trial is registered with ISRCTN, ISRCTN17545443.FindingsBetween Nov 14, 2017, and July 29, 2019, 252 patients were screened, 140 patients were randomly assigned, and 130 started a treatment pathway (with 84 completing at least two pathways) and were analysed for the primary outcome. The 7-day average NRS scores at week 16 decreased from a mean 6·6 (SD 1·5) at baseline to 3·3 (1·8) at week 16 in all three pathways. The mean difference was –0·1 (98·3% CI –0·5 to 0·3) for D-P versus A-P, –0·1 (–0·5 to 0·3) for P-A versus A-P, and 0·0 (–0·4 to 0·4) for P-A versus D-P, and thus not significant. Mean NRS reduction in patients on combination therapy was greater than in those who remained on monotherapy (1·0 [SD 1·3] vs 0·2 [1·5]). Adverse events were predictable for the monotherapies: we observed a significant increase in dizziness in the P-A pathway, nausea in the D-P pathway, and dry mouth in the A-P pathway.InterpretationTo our knowledge, this was the largest and longest ever, head-to-head, crossover neuropathic pain trial. We showed that all three treatment pathways and monotherapies had similar analgesic efficacy. Combination treatment was well tolerated and led to improved pain relief in patients with suboptimal pain control with a monotherapy.FundingNational Institute for Health Research (NIHR) Health Technology Assessment programme.

Rehabilitation versus surgical reconstruction for non-acute anterior cruciate ligament injury (ACL SNNAP): a pragmatic randomised controlled trial

Anterior cruciate ligament (ACL) rupture is a common debilitating injury that can cause instability of the knee. We aimed to investigate the best management strategy between reconstructive surgery and non-surgical treatment for patients with a non-acute ACL injury and persistent symptoms of instability. We did a pragmatic, multicentre, superiority, randomised controlled trial in 29 secondary care National Health Service orthopaedic units in the UK. Patients with symptomatic knee problems (instability) consistent with an ACL injury were eligible. We excluded patients with meniscal pathology with characteristics that indicate immediate surgery. Patients were randomly assigned (1:1) by computer to either surgery (reconstruction) or rehabilitation (physiotherapy but with subsequent reconstruction permitted if instability persisted after treatment), stratified by site and baseline Knee Injury and Osteoarthritis Outcome Score-4 domain version (KOOS4). This management design represented normal practice. The primary outcome was KOOS4 at 18 months after randomisation. The principal analyses were intention-to-treat based, with KOOS4 results analysed using linear regression. This trial is registered with ISRCTN, ISRCTN10110685, and ClinicalTrials.gov, NCT02980367. Between Feb 1, 2017, and April 12, 2020, we recruited 316 patients. 156 (49%) participants were randomly assigned to the surgical reconstruction group and 160 (51%) to the rehabilitation group. Mean KOOS4 at 18 months was 73·0 (SD 18·3) in the surgical group and 64·6 (21·6) in the rehabilitation group. The adjusted mean difference was 7·9 (95% CI 2·5-13·2; p=0·0053) in favour of surgical management. 65 (41%) of 160 patients allocated to rehabilitation underwent subsequent surgery according to protocol within 18 months. 43 (28%) of 156 patients allocated to surgery did not receive their allocated treatment. We found no differences between groups in the proportion of intervention-related complications. Surgical reconstruction as a management strategy for patients with non-acute ACL injury with persistent symptoms of instability was clinically superior and more cost-effective in comparison with rehabilitation management. The UK National Institute for Health Research Health Technology Assessment Programme.

Offer of a bandage versus rigid immobilisation in 4- to 15-year-olds with distal radius torus fractures: the FORCE equivalence RCT.

Torus (buckle) fractures of the wrist are the most common fractures in children involving the distal radius and/or ulna. It is unclear if children require rigid immobilisation and follow-up or would recover equally as well by being discharged without any immobilisation or a bandage. Given the large number of these injuries, identifying the optimal treatment strategy could have important effects on the child, the number of days of school absence and NHS costs. To establish whether or not treating children with a distal radius torus fracture with the offer of a soft bandage and immediate discharge (i.e. offer of a bandage) provides the same recovery, in terms of pain, function, complications, acceptability, school absence and resource use, as treatment with rigid immobilisation and follow-up as per usual practice (i.e. rigid immobilisation). A pragmatic, multicentre, randomised controlled equivalence trial. Twenty-three UK emergency departments. A total of 965 children (aged 4-15 years) with a distal radius torus fracture were randomised from January 2019 to July 2020 using a secure, centralised, online-encrypted randomisation service. Exclusion criteria included presentation > 36 hours after injury, multiple injuries and an inability to complete follow-up. A bandage was offered to 489 participants and applied to 458, and rigid immobilisation was carried out in 476 participants. Participants and clinicians were not blinded to the treatment allocation. The pain at 3 days post randomisation was measured using the Wong-Baker FACES Pain Rating Scale. Secondary outcomes were the patient-reported outcomes measurement system upper extremity limb score for children, health-related quality of life, complications, school absence, analgesia use and resource use collected up to 6 weeks post randomisation. A total of 94% of participants provided primary outcome data. At 3 days, the primary outcome of pain was equivalent in both groups. With reference to the prespecified equivalence margin of 1.0, the adjusted difference in the intention-to-treat population was -0.10 (95% confidence interval -0.37 to 0.17) and the per-protocol population was -0.06 (95% confidence interval -0.34 to 0.21). There was equivalence of pain in both age subgroups (i.e. 4-7 years and 8-15 years). There was no difference in the rate of complications, with five complications (1.0%) in the offer of a bandage group and three complications (0.6%) in the rigid immobilisation group. There were no differences between treatment groups in functional recovery, quality of life or school absence at any point during the follow-up. Analgesia use was marginally higher at day 1 in the offer of a bandage group than it was in the rigid immobilisation group (83% vs. 78% of participants), but there was no difference at other time points. The offer of a bandage significantly reduced the cost of treatment and had a high probability of cost-effectiveness at a willingness-to-pay threshold of £30,000 per quality-adjusted life-year. Families had a strong pre-existing preference for the rigid immobilisation treatment. Given this, and the inability to blind families to the treatment allocation, observer bias was a concern. However, there was clear evidence of equivalence. The study findings support the offer of a bandage in children with a distal radius torus fracture. A clinical decision tool to determine which children require radiography is an important next step to prevent overtreatment of minor wrist fractures. There is also a need to rationalise interventions for other common childhood injuries (e.g. 'toddler's fractures' of the tibia). This trial is registered as ISRCTN13955395 and UKCRN Portfolio 39678. 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. 33. See the NIHR Journals Library website for further project information.

Deprescribing medicines in older people living with multimorbidity and polypharmacy: the TAILOR evidence synthesis.

Tackling problematic polypharmacy requires tailoring the use of medicines to individual needs and circumstances. This may involve stopping medicines (deprescribing) but patients and clinicians report uncertainty on how best to do this. The TAILOR medication synthesis sought to help understand how best to support deprescribing in older people living with multimorbidity and polypharmacy. We identified two research questions: (1) what evidence exists to support the safe, effective and acceptable stopping of medication in this patient group, and (2) how, for whom and in what contexts can safe and effective tailoring of clinical decisions related to medication use work to produce desired outcomes? We thus described three objectives: (1) to undertake a robust scoping review of the literature on stopping medicines in this group to describe what is being done, where and for what effect; (2) to undertake a realist synthesis review to construct a programme theory that describes 'best practice' and helps explain the heterogeneity of deprescribing approaches; and (3) to translate findings into resources to support tailored prescribing in clinical practice. Experienced information specialists conducted comprehensive searches in MEDLINE, Cumulative Index to Nursing and Allied Health Literature, Web of Science, EMBASE, The Cochrane Library (Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials), Joanna Briggs Institute Database of Systematic Reviews and Implementation Reports, Google (Google Inc., Mountain View, CA, USA) and Google Scholar (targeted searches). The scoping review followed the five steps described by the Joanna Briggs Institute methodology for conducting a scoping review. The realist review followed the methodological and publication standards for realist reviews described by the Realist And Meta-narrative Evidence Syntheses: Evolving Standards (RAMESES) group. Patient and public involvement partners ensured that our analysis retained a patient-centred focus. Our scoping review identified 9528 abstracts: 8847 were removed at screening and 662 were removed at full-text review. This left 20 studies (published between 2009 and 2020) that examined the effectiveness, safety and acceptability of deprescribing in adults (aged ≥ 50 years) with polypharmacy (five or more prescribed medications) and multimorbidity (two or more conditions). Our analysis revealed that deprescribing under research conditions mapped well to expert guidance on the steps needed for good clinical practice. Our findings offer evidence-informed support to clinicians regarding the safety, clinician acceptability and potential effectiveness of clinical decision-making that demonstrates a structured approach to deprescribing decisions. Our realist review identified 2602 studies with 119 included in the final analysis. The analysis outlined 34 context-mechanism-outcome configurations describing the knowledge work of tailored prescribing under eight headings related to organisational, health-care professional and patient factors, and interventions to improve deprescribing. We conclude that robust tailored deprescribing requires attention to providing an enabling infrastructure, access to data, tailored explanations and trust. Strict application of our definition of multimorbidity during the scoping review may have had an impact on the relevance of the review to clinical practice. The realist review was limited by the data (evidence) available. Our combined reviews recognise deprescribing as a complex intervention and provide support for the safety of structured approaches to deprescribing, but also highlight the need to integrate patient-centred and contextual factors into best practice models. The TAILOR study has informed new funded research tackling deprescribing in sleep management, and professional education. Further research is being developed to implement tailored prescribing into routine primary care practice. This study is registered as PROSPERO CRD42018107544 and PROSPERO CRD42018104176. 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. 32. See the NIHR Journals Library website for further project information.

Systematic voiding programme in adults with urinary incontinence following acute stroke: the ICONS-II RCT.

Urinary incontinence affects around half of stroke survivors in the acute phase, and it often presents as a new problem after stroke or, if pre-existing, worsens significantly, adding to the disability and helplessness caused by neurological deficits. New management programmes after stroke are needed to address urinary incontinence early and effectively. The Identifying Continence OptioNs after Stroke (ICONS)-II trial aimed to evaluate the clinical effectiveness and cost-effectiveness of a systematic voiding programme for urinary incontinence after stroke in hospital. This was a pragmatic, multicentre, individual-patient-randomised (1 : 1), parallel-group trial with an internal pilot. Eighteen NHS stroke services with stroke units took part. Participants were adult men and women with acute stroke and urinary incontinence, including those with cognitive impairment. Participants were randomised to the intervention, a systematic voiding programme, or to usual care. The systematic voiding programme comprised assessment, behavioural interventions (bladder training or prompted voiding) and review. The assessment included evaluation of the need for and possible removal of an indwelling urinary catheter. The intervention began within 24 hours of recruitment and continued until discharge from the stroke unit. The primary outcome measure was severity of urinary incontinence (measured using the International Consultation on Incontinence Questionnaire) at 3 months post randomisation. Secondary outcome measures were taken at 3 and 6 months after randomisation and on discharge from the stroke unit. They included severity of urinary incontinence (at discharge and at 6 months), urinary symptoms, number of urinary tract infections, number of days indwelling urinary catheter was in situ, functional independence, quality of life, falls, mortality rate and costs. The trial statistician remained blinded until clinical effectiveness analysis was complete. The planned sample size was 1024 participants, with 512 allocated to each of the intervention and the usual-care groups. The internal pilot did not meet the target for recruitment and was extended to March 2020, with changes made to address low recruitment. The trial was paused in March 2020 because of COVID-19, and was later stopped, at which point 157 participants had been randomised (intervention, n = 79; usual care, n = 78). There were major issues with attrition, with 45% of the primary outcome data missing: 56% of the intervention group data and 35% of the usual-care group data. In terms of the primary outcome, patients allocated to the intervention group had a lower score for severity of urinary incontinence (higher scores indicate greater severity in urinary incontinence) than those allocated to the usual-care group, with means (standard deviations) of 8.1 (7.4) and 9.1 (7.8), respectively. The trial was unable to recruit sufficient participants and had very high attrition, which resulted in seriously underpowered results. The internal pilot did not meet its target for recruitment and, despite recruitment subsequently being more promising, it was concluded that the trial was not feasible owing to the combined problems of poor recruitment, poor retention and COVID-19. The intervention group had a slightly lower score for severity of urinary incontinence at 3 months post randomisation, but this result should be interpreted with caution. Further studies to assess the effectiveness of an intervention starting in or continuing into the community are required. This trial is registered as ISRCTN14005026. 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. 31. See the NIHR Journals Library website for further project information.

Sensory integration therapy for children with autism and sensory processing difficulties: the SenITA RCT.

Carers report unmet need for occupational therapy services addressing sensory difficulties in autism, yet insufficient evidence exists to recommend a therapeutic approach. Our aim was to determine the clinical effectiveness and cost-effectiveness of sensory integration therapy for children with autism and sensory difficulties across behavioural, functional and quality-of-life outcomes. We carried out a parallel-group randomised controlled trial, incorporating an internal pilot and a process evaluation. Randomisation utilised random permuted blocks. Children were recruited via services and self-referral in Wales and England. Inclusion criteria were having an autism diagnosis, being in mainstream primary education and having definite/probable sensory processing difficulties. Exclusion criteria were having current/previous sensory integration therapy and current applied behaviour analysis therapy. The intervention was manualised sensory integration therapy delivered over 26 weeks and the comparator was usual care. The primary outcome was problem behaviours (determined using the Aberrant Behavior Checklist), including irritability/agitation, at 6 months. Secondary outcomes were adaptive behaviour, functioning and socialisation (using the Vineland Adaptive Behavior Scales); carer stress (measured using the Autism Parenting Stress Index); quality of life (measured using the EuroQol-5 Dimensions and Carer Quality of Life); functional change (according to the Canadian Occupational Performance Measure); sensory processing (determined using the Sensory Processing Measure™ at screening and at 6 months to examine mediation effects); and cost-effectiveness (assessed using the Client Service Receipt Inventory). Every effort was made to ensure that outcome assessors were blind to allocation. A total of 138 participants were randomised (n = 69 per group). Usual care was significantly different from the intervention, which was delivered with good fidelity and adherence and minimal contamination, and was associated with no adverse effects. Trial procedures and outcome measures were acceptable. Carers and therapists reported improvement in daily functioning. The primary analysis included 106 participants. There were no significant main effects of the intervention at 6 or 12 months. The adjusted mean difference between groups on the Aberrant Behavior Checklist - irritability at 6 months post randomisation was 0.40 (95% confidence interval -2.33 to 3.14; p = 0.77). Subgroup differences in irritability/agitation at 6 months were observed for sex of child (intervention × female = 6.42, 95% confidence interval 0.00 to 12.85; p = 0.050) and attention deficit hyperactivity disorder (intervention × attention deficit hyperactivity disorder = -6.77, 95% confidence interval -13.55 to -0.01; p = 0.050). There was an effect on carer stress at 6 months by region (intervention × South England = 7.01, 95% confidence interval 0.45 to 13.56; p = 0.04) and other neurodevelopmental/genetic conditions (intervention × neurodevelopmental/genetic condition = -9.53, 95% confidence interval -18.08 to -0.98; p = 0.030). Carer-rated goal performance and satisfaction increased across sessions (p < 0.001), with a mean change of 2.75 (95% confidence interval 2.14 to 3.37) for performance and a mean change of 3.34 (95% confidence interval 2.63 to 4.40) for satisfaction. Health economic evaluation suggests that sensory integration therapy is not cost-effective compared with usual care alone. Limitations included variability of the intervention setting (i.e. NHS vs. private), delay for some receiving therapy, an error in administration of Vineland Adaptive Behavior Scales and no measurement of comparator arm goal performance. The intervention did not demonstrate clinical benefit above standard care. Subgroup effects are hypothesis-generating only. The intervention is likely to be effective for individualised performance goals, although it is unclear whether effects were in addition to standard care or were maintained. Further investigation of subgroup effects is needed. This trial is registered as ISRCTN14716440. 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. 29. See the NIHR Journals Library website for further project information.

Long-term impact of pre-incision antibiotics on children born by caesarean section: a longitudinal study based on UK electronic health records.

Since changes in the national guidance in 2011, prophylactic antibiotics for women undergoing caesarean section are recommended prior to skin incision, rather than after the baby's umbilical cord has been clamped. Evidence from randomised controlled trials conducted outside the UK has shown that this reduces maternal infectious morbidity; however, the prophylactic antibiotics also cross the placenta, meaning that babies are exposed to them around the time of birth. Antibiotics are known to affect the gut microbiota of the babies, but the long-term effects of exposure to high-dose broad-spectrum antibiotics around the time of birth on allergy and immune-related diseases are unknown. We aimed to examine whether or not in-utero exposure to antibiotics immediately prior to birth compared with no pre-incisional antibiotic exposure increases the risk of (1) asthma and (2) eczema in children born by caesarean section. This was a controlled interrupted time series study. The study took place in primary and secondary care. Children born in the UK during 2006-18 delivered by caesarean section were compared with a control cohort delivered vaginally. In-utero exposure to antibiotics immediately prior to birth. Asthma and eczema in children in the first 5 years of life. Additional secondary outcomes, including other allergy-related conditions, autoimmune diseases, infections, other immune system-related diseases and neurodevelopmental conditions, were also assessed. The Health Improvement Network (THIN) and the Clinical Practice Research Datalink (CPRD) primary care databases and the Hospital Episode Statistics (HES) database. Previously published linkage strategies were adapted to link anonymised data on mothers and babies in these databases. Duplicate practices contributing to both THIN and the CPRD databases were removed to create a THIN-CPRD data set. In the THIN-CPRD and HES data sets, records of 515,945 and 3,945,351 mother-baby pairs were analysed, respectively. The risk of asthma was not significantly higher in children born by caesarean section exposed to pre-incision antibiotics than in children whose mothers received post-cord clamping antibiotics, with an incidence rate ratio of 0.91 (95% confidence interval 0.78 to 1.05) for diagnosis of asthma in primary care and an incidence rate ratio of 1.05 (95% confidence interval 0.99 to 1.11) for asthma resulting in a hospital admission. We also did not find an increased risk of eczema, with an incidence rate ratio of 0.98 (95% confidence interval 0.94 to1.03) and an incidence rate ratio of 0.96 (95% confidence interval 0.71 to 1.29) for diagnosis in primary care and hospital admissions, respectively. It was not possible to ascertain the exposure to pre-incision antibiotics at an individual level. The maximum follow-up of children was 5 years. There was no evidence that the policy change from post-cord clamping to pre-incision prophylactic antibiotics for caesarean sections during 2006-18 had an impact on the incidence of asthma and eczema in early childhood in the UK. There is a need for further research to investigate if pre-incision antibiotics have any impact on developing asthma and other allergy and immune-related conditions in older children. This study is registered as researchregistry3736. 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. 30. See the NIHR Journals Library website for further project information.