Nasal sprays and behavioural interventions compared with usual care for acute respiratory illness in primary care: a randomised, controlled, open-label, parallel-group trial.

BACKGROUND: A small amount of evidence suggests that nasal sprays, or physical activity and stress management, could shorten the duration of respiratory infections. This study aimed to assess the effect of nasal sprays or a behavioural intervention promoting physical activity and stress management on respiratory illnesses, compared with usual care. METHODS: This randomised, controlled, open-label, parallel-group trial was done at 332 general practitioner practices in the UK. Eligible adults (aged ≥18 years) had at least one comorbidity or risk factor increasing their risk of adverse outcomes due to respiratory illness (eg, immune compromise due to serious illness or medication; heart disease; asthma or lung disease; diabetes; mild hepatic impairment; stroke or severe neurological problem; obesity [BMI ≥30 kg/m2]; or age ≥65 years) or at least three self-reported respiratory tract infections in a normal year (ie, any year before the COVID-19 pandemic). Participants were randomly assigned (1:1:1:1) using a computerised system to: usual care (brief advice about managing illness); gel-based spray (two sprays per nostril at the first sign of an infection or after potential exposure to infection, up to 6 times per day); saline spray (two sprays per nostril at the first sign of an infection or after potential exposure to infection, up to 6 times per day); or a brief behavioural intervention in which participants were given access to a website promoting physical activity and stress management. The study was partially masked: neither investigators nor medical staff were aware of treatment allocation, and investigators who did the statistical analysis were unaware of treatment allocation. The sprays were relabelled to maintain participant masking. Outcomes were assessed using data from participants' completed monthly surveys and a survey at 6 months. The primary outcome was total number of days of illness due to self-reported respiratory tract illnesses (coughs, colds, sore throat, sinus or ear infections, influenza, or COVID-19) in the previous 6 months, assessed in the modified intention-to-treat population, which included all randomly assigned participants who had primary outcome data available. Key secondary outcomes were possible harms, including headache or facial pain, and antibiotic use, assessed in all randomly assigned participants. This trial was registered with ISRCTN, 17936080, and is closed to recruitment. FINDINGS: Between Dec 12, 2020, and April 7, 2023, of 19 475 individuals screened for eligibility, 13 799 participants were randomly assigned to usual care (n=3451), gel-based nasal spray (n=3448), saline nasal spray (n=3450), or the digital intervention promoting physical activity and stress management (n=3450). 11 612 participants had complete data for the primary outcome and were included in the primary outcome analysis (usual care group, n=2983; gel-based spray group, n=2935; saline spray group, n=2967; behavioural website group, n=2727). Compared with participants in the usual care group, who had a mean of 8·2 (SD 16·1) days of illness, the number of days of illness was significantly lower in the gel-based spray group (mean 6·5 days [SD 12·8]; adjusted incidence rate ratio [IRR] 0·82 [99% CI 0·76-0·90]; p<0·0001) and the saline spray group (6·4 days [12·4]; 0·81 [0·74-0·88]; p<0·0001), but not in the group allocated to the behavioural website (7·4 days [14·7]; 0·97 [0·89-1·06]; p=0·46). The most common adverse event was headache or sinus pain in the gel-based group: 123 (4·8%) of 2556 participants in the usual care group; 199 (7·8%) of 2498 participants in the gel-based group (risk ratio 1·61 [95% CI 1·30-1·99]; p<0·0001); 101 (4·5%) of 2377 participants in the saline group (0·81 [0·63-1·05]; p=0·11); and 101 (4·5%) of 2091 participants in the behavioural intervention group (0·95 [0·74-1·22]; p=0·69). Compared with usual care, antibiotic use was lower for all interventions: IRR 0·65 (95% CI 0·50-0·84; p=0·001) for the gel-based spray group; 0·69 (0·45-0·88; p=0·003) for the saline spray group; and 0·74 (0·57-0·94; p=0·02) for the behavioural website group. INTERPRETATION: Advice to use either nasal spray reduced illness duration and both sprays and the behavioural website reduced antibiotic use. Future research should aim to address the impact of the widespread implementation of these simple interventions. FUNDING: National Institute for Health and Care Research.

Emollient application from birth to prevent eczema in high-risk children: the BEEP RCT.

Background: Atopic eczema is a common childhood skin problem linked with asthma, food allergy and allergic rhinitis that impairs quality of life. Objectives: To determine whether advising parents to apply daily emollients in the first year can prevent eczema and/or other atopic diseases in high-risk children. Design: A United Kingdom, multicentre, pragmatic, two-arm, parallel-group randomised controlled prevention trial with follow-up to 5 years. Setting: Twelve secondary and four primary care centres. Participants: Healthy infants (at least 37 weeks' gestation) at high risk of developing eczema, screened and consented during the third trimester or post delivery. Interventions: Infants were randomised (1 : 1) within 21 days of birth to apply emollient (Doublebase Gel®; Dermal Laboratories Ltd, Hitchin, UK or Diprobase Cream®) daily to the whole body (excluding scalp) for the first year, plus standard skin-care advice (emollient group) or standard skin-care advice only (control group). Families were not blinded to allocation. Main outcome measures: Primary outcome was eczema diagnosis in the last year at age 2 years, as defined by the UK Working Party refinement of the Hanifin and Rajka diagnostic criteria, assessed by research nurses blinded to allocation. Secondary outcomes up to age 2 years included other eczema definitions, time to onset and severity of eczema, allergic rhinitis, wheezing, allergic sensitisation, food allergy, safety (skin infections and slippages) and cost-effectiveness. Results: One thousand three hundred and ninety-four newborns were randomised between November 2014 and November 2016; 693 emollient and 701 control. Adherence in the emollient group was 88% (466/532), 82% (427/519) and 74% (375/506) at 3, 6 and 12 months. At 2 years, eczema was present in 139/598 (23%) in the emollient group and 150/612 (25%) in controls (adjusted relative risk 0.95, 95% confidence interval 0.78 to 1.16; p = 0.61 and adjusted risk difference -1.2%, 95% confidence interval -5.9% to 3.6%). Other eczema definitions supported the primary analysis. Food allergy (milk, egg, peanut) was present in 41/547 (7.5%) in the emollient group versus 29/568 (5.1%) in controls (adjusted relative risk 1.47, 95% confidence interval 0.93 to 2.33). Mean number of skin infections per child in the first year was 0.23 (standard deviation 0.68) in the emollient group versus 0.15 (standard deviation 0.46) in controls; adjusted incidence rate ratio 1.55, 95% confidence interval 1.15 to 2.09. The adjusted incremental cost per percentage decrease in risk of eczema at 2 years was £5337 (£7281 unadjusted). No difference between the groups in eczema or other atopic diseases was observed during follow-up to age 5 years via parental questionnaires. Limitations: Two emollient types were used which could have had different effects. The median time for starting emollients was 11 days after birth. Some contamination occurred in the control group (< 20%). Participating families were unblinded and reported on some outcomes. Conclusions: We found no evidence that daily emollient during the first year of life prevents eczema in high-risk children. Emollient use was associated with a higher risk of skin infections and a possible increase in food allergy. Emollient use is unlikely to be considered cost-effective in this context. Future research: To pool similar studies in an individual patient data meta-analysis. Trial registration: This trial is registered as ISRCTN21528841. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 12/67/12) and is published in full in Health Technology Assessment; Vol. 28, No. 29. See the NIHR Funding and Awards website for further award information.

Eczema is a troublesome itchy skin condition affecting 1 in 5 children and 1 in 10 UK adults. There is no cure and affected children are more likely to develop food allergies. We wanted to see if we could prevent eczema by protecting the skin of babies at higher risk of developing eczema (with an immediate relative with eczema, asthma or hay fever) with moisturisers used to treat dry skin. Previous research suggested that protecting the skin barrier might also prevent food allergy. One thousand three hundred and ninety-four families took part in a study; half of them were asked to apply moisturiser every day to their newborn baby for the first year and half to look after their baby's skin in the normal way. At the age of 2 years, we did not see any difference in how common eczema was between the two groups: 23% had eczema in the moisturiser group and 25% in the normal care group. It did not matter how we defined eczema ­ whether examined by a researcher or parent report. We did not find any differences in related conditions like asthma or hay fever either. We found that children using moisturisers had seen their doctor slightly more often for mild skin infections. There was a hint that food allergy might have been increased in the moisturiser group, but there was not enough data to be sure. We followed up the children to age 5 years, but we still did not find any benefits from using moisturisers in early life. Since this study, other similar research has been done using newer types of moisturisers, but their results are the same. This study shows that using daily moisturisers on healthy babies with a high risk of eczema does not prevent eczema. It is one less thing for busy families to worry about.

Online behavioural interventions for children and young people with eczema: a quantitative evaluation.

BACKGROUND: Two online behavioural interventions (one website for parents/carers of children with eczema; and one for young people with eczema) have been shown in randomised controlled trials to facilitate a sustained improvement in eczema severity. AIM: To describe intervention use and examine potential mediators of intervention outcomes and contextual factors that may influence intervention delivery and outcomes. DESIGN AND SETTING: Quantitative process evaluation in UK primary care. METHOD: Parents/carers and young people were recruited through primary care. Intervention use was recorded and summarised descriptively. Logistic regression explored sociodemographic and other factors associated with intervention engagement. Mediation analysis investigated whether patient enablement (ability to understand and cope with health issues), treatment use, and barriers to adherence were mediators of intervention effect. Subgroup analysis compared intervention effects among pre-specified participant subsets. RESULTS: A total of 340 parents/carers and 337 young people were recruited. Most parents/carers (87%, n = 148/171) and young people (91%, n = 153/168) in the intervention group viewed the core introduction by 24 weeks. At 24 weeks, users had spent approximately 20 minutes on average on the interventions. Among parents/carers, greater intervention engagement was associated with higher education levels, uncertainty about carrying out treatments, and doubts about treatment efficacy at baseline. Among young people, higher intervention use was associated with higher baseline eczema severity. Patient enablement (the ability to understand and cope with health issues) accounted for approximately 30% of the intervention effect among parents/carers and 50% among young people. CONCLUSION: This study demonstrated that positive intervention outcomes depended on a modest time commitment from users. This provides further support that the wider implementation of Eczema Care Online is justified.

Cost-effectiveness of two online interventions supporting self-care for eczema for parents/carers and young people.

OBJECTIVE: To estimate the cost-effectiveness of online behavioral interventions (EczemaCareOnline.org.uk) designed to support eczema self-care management for parents/carers and young people from an NHS perspective. METHODS: Two within-trial economic evaluations, using regression-based approaches, adjusting for baseline and pre-specified confounder variables, were undertaken alongside two independent, pragmatic, parallel group, unmasked randomized controlled trials, recruiting through primary care. Trial 1 recruited 340 parents/carers of children aged 0-12 years and Trial 2 337 young people aged 13-25 years with eczema scored ≥ 5 on Patient-Oriented Eczema Measure (POEM). Participants were randomized (1:1) to online intervention plus usual care or usual care alone. Resource use, collected via medical notes review, was valued using published unit costs in UK £Sterling 2021. Quality-of-life was elicited using proxy CHU-9D in Trial 1 and self-report EQ-5D-5L in Trial 2. RESULTS: The intervention was dominant (cost saving and more effective) with a high probability of cost-effectiveness (> 68%) in most analyses. The exception was the complete case cost-utility analysis for Trial 1 (omitting participants with children aged < 2), with adjusted incremental cost savings of -£34.15 (95% CI - 104.54 to 36.24) and incremental QALYs of - 0.003 (95% CI - 0.021 to 0.015) producing an incremental cost per QALY of £12,466. In the secondary combined (Trials 1 and 2) cost-effectiveness analysis, the adjusted incremental cost was -£20.35 (95% CI - 55.41 to 14.70) with incremental success (≥ 2-point change on POEM) of 10.3% (95% CI 2.3-18.1%). CONCLUSION: The free at point of use online eczema self-management intervention was low cost to run and cost-effective. TRIAL REGISTRATION: This trial was registered prospectively with the ISRCTN registry (ISRCTN79282252). URL www.EczemaCareOnline.org.uk .

Cost-effectiveness of Spironolactone for Adult Female Acne (SAFA): economic evaluation alongside a randomised controlled trial.

OBJECTIVE: This study aims to estimate the cost-effectiveness of oral spironolactone plus routine topical treatment compared with routine topical treatment alone for persistent acne in adult women from a British NHS perspective over 24 weeks. DESIGN: Economic evaluation undertaken alongside a pragmatic, parallel, double-blind, randomised trial. SETTING: Primary and secondary healthcare, community and social media advertising. PARTICIPANTS: Women ≥18 years with persistent facial acne judged to warrant oral antibiotic treatment. INTERVENTIONS: Participants were randomised 1:1 to 50 mg/day spironolactone (increasing to 100 mg/day after 6 weeks) or matched placebo until week 24. Participants in both groups could continue topical treatment. MAIN OUTCOME MEASURES: Cost-utility analysis assessed incremental cost per quality-adjusted life year (QALY) using the EQ-5D-5L. Cost-effectiveness analysis estimated incremental cost per unit change on the Acne-QoL symptom subscale. Adjusted analysis included randomisation stratification variables (centre, baseline severity (investigator's global assessment, IGA <3 vs ≥3)) and baseline variables (Acne-QoL symptom subscale score, resource use costs, EQ-5D score and use of topical treatments). RESULTS: Spironolactone did not appear cost-effective in the complete case analysis (n=126 spironolactone, n=109 control), compared with no active systemic treatment (adjusted incremental cost per QALY £67 191; unadjusted £34 770). Incremental cost per QALY was £27 879 (adjusted), just below the upper National Institute for Health and Care Excellence's threshold value of £30 000, where multiple imputation took account of missing data. Incremental cost per QALY for other sensitivity analyses varied around the base-case, highlighting the degree of uncertainty. The adjusted incremental cost per point change on the Acne-QoL symptom subscale for spironolactone compared with no active systemic treatment was £38.21 (complete case analysis). CONCLUSIONS: The results demonstrate a high level of uncertainty, particularly with respect to estimates of incremental QALYs. Compared with no active systemic treatment, spironolactone was estimated to be marginally cost-effective where multiple imputation was performed but was not cost-effective in complete case analysis. TRIAL REGISTRATION NUMBER: ISRCTN registry (ISRCTN12892056).

Efficacy and safety of ciclosporin versus methotrexate in the treatment of severe atopic dermatitis in children and young people (TREAT): a multicentre parallel group assessor-blinded clinical trial.

BACKGROUND: Conventional systemic drugs are used to treat children and young people (CYP) with severe atopic dermatitis (AD) worldwide, but no robust randomized controlled trial (RCT) evidence exists regarding their efficacy and safety in this population. While novel therapies have expanded therapeutic options, their high cost means traditional agents remain important, especially in lower-resource settings. OBJECTIVES: To compare the safety and efficacy of ciclosporin (CyA) with methotrexate (MTX) in CYP with severe AD in the TREatment of severe Atopic Eczema Trial (TREAT) trial. METHODS: We conducted a parallel group assessor-blinded RCT in 13 UK and Irish centres. Eligible participants aged 2-16 years and unresponsive to potent topical treatment were randomized to either oral CyA (4 mg kg-1 daily) or MTX (0.4 mg kg-1 weekly) for 36 weeks and followed-up for 24 weeks. Co-primary outcomes were change from baseline to 12 weeks in Objective Severity Scoring of Atopic Dermatitis (o-SCORAD) and time to first significant flare (relapse) after treatment cessation. Secondary outcomes included change in quality of life (QoL) from baseline to 60 weeks; number of participant-reported flares following treatment cessation; proportion of participants achieving ≥ 50% improvement in Eczema Area and Severity Index (EASI 50) and ≥ 75% improvement in EASI (EASI 75); and stratification of outcomes by filaggrin status. RESULTS: In total, 103 participants were randomized (May 2016-February 2019): 52 to CyA and 51 to MTX. CyA showed greater improvement in disease severity by 12 weeks [mean difference in o-SCORAD -5.69, 97.5% confidence interval (CI) -10.81 to -0.57 (P = 0.01)]. More participants achieved ≥ 50% improvement in o-SCORAD (o-SCORAD 50) at 12 weeks in the CyA arm vs. the MTX arm [odds ratio (OR) 2.60, 95% CI 1.23-5.49; P = 0.01]. By 60 weeks MTX was superior (OR 0.33, 95% CI 0.13-0.85; P = 0.02), a trend also seen for ≥ 75% improvement in o-SCORAD (o-SCORAD 75), EASI 50 and EASI 75. Participant-reported flares post-treatment were higher in the CyA arm (OR 3.22, 95% CI 0.42-6.01; P = 0.02). QoL improved with both treatments and was sustained after treatment cessation. Filaggrin status did not affect outcomes. The frequency of adverse events (AEs) was comparable between both treatments. Five (10%) participants on CyA and seven (14%) on MTX experienced a serious AE. CONCLUSIONS: Both CyA and MTX proved effective in CYP with severe AD over 36 weeks. Participants who received CyA showed a more rapid response to treatment, while MTX induced more sustained disease control after discontinuation.

Emollients for preventing atopic eczema: Cost-effectiveness analysis of the BEEP trial.

BACKGROUND: Recent discoveries have led to the suggestion that enhancing skin barrier from birth might prevent eczema and food allergy. OBJECTIVE: To determine the cost-effectiveness of daily all-over-body application of emollient during the first year of life for preventing atopic eczema in high-risk children at 2 years from a health service perspective. We also considered a 5-year time horizon as a sensitivity analysis. METHODS: A within-trial economic evaluation using data on health resource use and quality of life captured as part of the BEEP trial alongside the trial data. Parents/carers of 1394 infants born to families at high risk of atopic disease were randomised 1:1 to the emollient group, which were advised to apply emollient (Doublebase Gel or Diprobase Cream) to their child at least once daily to the whole body during the first year of life or usual care. Both groups received advice on general skin care. The main economic outcomes were incremental cost-effectiveness ratio (ICER), defined as incremental cost per percentage decrease in risk of eczema in the primary cost-effectiveness analysis. Secondary analysis, undertaken as a cost-utility analysis, reports incremental cost per Quality-Adjusted Life Year (QALY) where child utility was elicited using the proxy CHU-9D at 2 years. RESULTS: At 2 years, the adjusted incremental cost was £87.45 (95% CI -54.31, 229.27) per participant, whilst the adjusted proportion without eczema was 0.0164 (95% CI -0.0329, 0.0656). The ICER was £5337 per percentage decrease in risk of eczema. Adjusted incremental QALYs were very slightly improved in the emollient group, 0.0010 (95% CI -0.0069, 0.0089). At 5 years, adjusted incremental costs were lower for the emollient group, -£106.89 (95% CI -354.66, 140.88) and the proportion without eczema was -0.0329 (95% CI -0.0659, 0.0002). The 5-year ICER was £3201 per percentage decrease in risk of eczema. However, when inpatient costs due to wheezing were excluded, incremental costs were lower and incremental effects greater in the usual care group. CONCLUSIONS: In line with effectiveness endpoints, advice given in the BEEP trial to apply daily emollient during infancy for eczema prevention in high-risk children does not appear cost-effective.

Effectiveness of spironolactone for women with acne vulgaris (SAFA) in England and Wales: pragmatic, multicentre, phase 3, double blind, randomised controlled trial.

OBJECTIVE: To assess the effectiveness of oral spironolactone for acne vulgaris in adult women. DESIGN: Pragmatic, multicentre, phase 3, double blind, randomised controlled trial. SETTING: Primary and secondary healthcare, and advertising in the community and on social media in England and Wales. PARTICIPANTS: Women (≥18 years) with facial acne for at least six months, judged to warrant oral antibiotics. INTERVENTIONS: Participants were randomly assigned (1:1) to either 50 mg/day spironolactone or matched placebo until week six, increasing to 100 mg/day spironolactone or placebo until week 24. Participants could continue using topical treatment. MAIN OUTCOME MEASURES: Primary outcome was Acne-Specific Quality of Life (Acne-QoL) symptom subscale score at week 12 (range 0-30, where higher scores reflect improved QoL). Secondary outcomes were Acne-QoL at week 24, participant self-assessed improvement; investigator's global assessment (IGA) for treatment success; and adverse reactions. RESULTS: From 5 June 2019 to 31 August 2021, 1267 women were assessed for eligibility, 410 were randomly assigned to the intervention (n=201) or control group (n=209) and 342 were included in the primary analysis (n=176 in the intervention group and n=166 in the control group). Baseline mean age was 29.2 years (standard deviation 7.2), 28 (7%) of 389 were from ethnicities other than white, with 46% mild, 40% moderate, and 13% severe acne. Mean Acne-QoL symptom scores at baseline were 13.2 (standard deviation 4.9) and at week 12 were 19.2 (6.1) for spironolactone and 12.9 (4.5) and 17.8 (5.6) for placebo (difference favouring spironolactone 1.27 (95% confidence interval 0.07 to 2.46), adjusted for baseline variables). Scores at week 24 were 21.2 (5.9) for spironolactone and 17.4 (5.8) for placebo (difference 3.45 (95% confidence interval 2.16 to 4.75), adjusted). More participants in the spironolactone group reported acne improvement than in the placebo group: no significant difference was reported at week 12 (72% v 68%, odds ratio 1.16 (95% confidence interval 0.70 to 1.91)) but significant difference was noted at week 24 (82% v 63%, 2.72 (1.50 to 4.93)). Treatment success (IGA classified) at week 12 was 31 (19%) of 168 given spironolactone and nine (6%) of 160 given placebo (5.18 (2.18 to 12.28)). Adverse reactions were slightly more common in the spironolactone group with more headaches reported (20% v 12%; p=0.02). No serious adverse reactions were reported. CONCLUSIONS: Spironolactone improved outcomes compared with placebo, with greater differences at week 24 than week 12. Spironolactone is a useful alternative to oral antibiotics for women with acne. TRIAL REGISTRATION: ISRCTN12892056.

'Eczema shouldn't control you; you should control eczema': qualitative process evaluation of online behavioural interventions to support young people and parents/carers of children with eczema.

BACKGROUND: There is a lack of well-conducted randomized controlled trials evaluating the effectiveness of theory-based online interventions for eczema. To address these deficiencies, we previously developed and demonstrated the effectiveness of two online behavioural interventions: Eczema Care Online for parents/carers of children with eczema, and Eczema Care Online for young people with eczema. OBJECTIVES: To explore the views and experiences of people who have used the Eczema Care Online interventions to provide insights into how the interventions worked and identify contextual factors that may impede users' engagement with the interventions. METHODS: Qualitative semistructured interviews were conducted with 17 parents/carers of children with eczema and 17 young people with eczema. Participants were purposively sampled from two randomized controlled trials of the interventions and recruited from GP surgeries in England. Transcripts were analysed using inductive thematic analysis, and intervention modifications were identified using the person-based approach table of changes method. RESULTS: Both young people and parents/carers found the interventions easy to use, relatable and trustworthy, and perceived that they helped them to manage their eczema, thus suggesting that Eczema Care Online may be acceptable to its target groups. Our analysis suggested that the interventions may reduce eczema severity by facilitating empowerment among its users, specifically through improved understanding of, and confidence in, eczema management, reduced treatment concerns, and improved treatment adherence and management of irritants/triggers. Reading about the experiences of others with eczema helped people to feel 'normal' and less alone. Some (mainly young people) expressed firmly held negative beliefs about topical corticosteroids, views that were not influenced by the intervention. Minor improvements to the design and navigation of the Eczema Care Online interventions and content changes were identified and made, ready for wider implementation. CONCLUSIONS: People with eczema and their families can benefit from reliable information, specifically information on the best and safest ways to use their eczema treatments early in their eczema journey. Together, our findings from this study and the corresponding trials suggest wider implementation of Eczema Care Online (EczemaCareOnline.org.uk) is justified.

Emollients for prevention of atopic dermatitis: 5-year findings from the BEEP randomized trial.

BACKGROUND: The effectiveness of emollients for preventing atopic dermatitis/eczema is controversial. The Barrier Enhancement for Eczema Prevention trial evaluated the effects of daily emollients during the first year of life on atopic dermatitis and atopic conditions to age 5 years. METHODS: 1394 term infants with a family history of atopic disease were randomized (1:1) to daily emollient plus standard skin-care advice (693 emollient group) or standard skin-care advice alone (701 controls). Long-term follow-up at ages 3, 4 and 5 years was via parental questionnaires. Main outcomes were parental report of a clinical diagnosis of atopic dermatitis and food allergy. RESULTS: Parents reported more frequent moisturizer application in the emollient group through to 5 years. A clinical diagnosis of atopic dermatitis between 12 and 60 months was reported for 188/608 (31%) in the emollient group and 178/631 (28%) in the control group (adjusted relative risk 1.10, 95% confidence interval 0.93 to 1.30). Although more parents in the emollient group reported food reactions in the previous year at 3 and 4 years, cumulative incidence of doctor-diagnosed food allergy by 5 years was similar between groups (92/609 [15%] emollients and 87/632 [14%] controls, adjusted relative risk 1.11, 95% confidence interval 0.84 to 1.45). Findings were similar for cumulative incidence of asthma and hay fever. CONCLUSIONS: Daily emollient application during the first year of life does not prevent atopic dermatitis, food allergy, asthma or hay fever.

Prescribing and using vitiligo treatments: lessons from a nested process evaluation within the HI-Light vitiligo randomized controlled trial.

BACKGROUND: The HI-Light Trial demonstrated that for active, limited vitiligo, combination treatment with potent topical corticosteroid (TCS) and handheld narrowband ultraviolet B offers a better treatment response than potent TCS alone. However, it is unclear how to implement these findings. AIM: We sought to answer three questions: (i) Can combination treatment be used safely and effectively by people with vitiligo?; (ii) Should combination treatment be made available as routine clinical care?; and (iii) Can combination treatment be integrated within current healthcare provision? METHODS: This was a mixed-methods process evaluation, including semi-structured interviews with a purposive sample of trial participants, structured interviews with commissioners, and an online survey and focus groups with trial staff. Transcripts were coded by framework analysis, with thematic development by multiple researchers. RESULTS: Participants found individual treatments easy to use, but the combination treatment was complicated and required nurse support. Both participants and site investigators felt that combination treatment should be made available, although commissioners were less certain. There was support for the development of services offering combination treatment, although this might not be prioritized above treatment for other conditions. A 'mixed economy' model was suggested, involving patients purchasing their own devices, although concerns regarding the safe use of treatments mean that training, monitoring and ongoing support are essential. The need for medical physics support may mean that a regional service is more practical. CONCLUSION: Combination treatment should be made available for people seeking treatment for vitiligo, but services require partnership with medical physics and ongoing training and support for patients.

RETurn to work After stroKE (RETAKE) Trial: protocol for a mixed-methods process evaluation using normalisation process theory.

OBJECTIVES: This mixed-method process evaluation underpinned by normalisation process theory aims to measure fidelity to the intervention, understand the social and structural context in which the intervention is delivered and identify barriers and facilitators to intervention implementation. SETTING: RETurn to work After stroKE (RETAKE) is a multicentre individual patient randomised controlled trial to determine whether Early Stroke Specialist Vocational Rehabilitation (ESSVR) plus usual care is a clinically and cost-effective therapy to facilitate return to work after stroke, compared with usual care alone. This protocol paper describes the embedded process evaluation. PARTICIPANTS AND OUTCOME MEASURES: Intervention training for therapists will be observed and use of remote mentor support reviewed through documentary analysis. Fidelity will be assessed through participant questionnaires and analysis of therapy records, examining frequency, duration and content of ESSVR sessions. To understand the influence of social and structural contexts, the process evaluation will explore therapists' attitudes towards evidence-based practice, competency to deliver the intervention and evaluate potential sources of contamination. Longitudinal case studies incorporating non-participant observations will be conducted with a proportion of intervention and usual care participants. Semistructured interviews with stroke survivors, carers, occupational therapists, mentors, service managers and employers will explore their experiences as RETAKE participants. Analysis of qualitative data will draw on thematic and framework approaches. Quantitative data analysis will include regression models and descriptive statistics. Qualitative and quantitative data will be independently analysed by process evaluation and Clinical Trials Research Unit teams, respectively. Linked data, for example, fidelity and describing usual care will be synthesised by comparing and integrating quantitative descriptive data with the qualitative findings. ETHICS AND DISSEMINATION: Approval obtained through the East Midlands-Nottingham 2 Research Ethics Committee (Ref: 18/EM/0019) and the National Health ServiceResearch Authority. Dissemination via journal publications, stroke conferences, social media and meetings with national Stroke clinical leads. TRIAL REGISTRATION NUMBER: ISRCTN12464275.

A multidomain decision support tool to prevent falls in older people: the FinCH cluster RCT.

BACKGROUND: Falls in care home residents are common, unpleasant, costly and difficult to prevent. OBJECTIVES: The objectives were to evaluate the clinical effectiveness and cost-effectiveness of the Guide to Action for falls prevention in Care Homes (GtACH) programme. DESIGN: A multicentre, cluster, parallel, 1 : 1 randomised controlled trial with embedded process evaluation and economic evaluation. Care homes were randomised on a 1 : 1 basis to the GtACH programme or usual care using a secure web-based randomisation service. Research assistants, participating residents and staff informants were blind to allocation at recruitment; research assistants were blind to allocation at follow-up. NHS Digital data were extracted blindly. SETTING: Older people's care homes from 10 UK sites. PARTICIPANTS: Older care home residents. INTERVENTION: The GtACH programme, which includes care home staff training, systematic use of a multidomain decision support tool and implementation of falls prevention actions, compared to usual falls prevention care. OUTCOMES: The primary trial outcome was the rate of falls per participating resident occurring during the 90-day period between 91 and 180 days post randomisation. The primary outcome for the cost-effectiveness analysis was the cost per fall averted, and the primary outcome for the cost-utility analysis was the incremental cost per quality adjusted life-year. Secondary outcomes included the rate of falls over days 0-90 and 181-360 post randomisation, activity levels, dependency and fractures. The number of falls per resident was compared between arms using a negative binomial regression model (generalised estimating equation). RESULTS: A total of 84 care homes were randomised: 39 to the GtACH arm and 45 to the control arm. A total of 1657 residents consented and provided baseline measures (mean age 85 years, 32% men). GtACH programme training was delivered to 1051 staff (71% of eligible staff) over 146 group sessions. Primary outcome data were available for 630 GtACH participants and 712 control participants. The primary outcome result showed an unadjusted incidence rate ratio of 0.57 (95% CI 0.45 to 0.71; p < 0.01) in favour of the GtACH programme. Falls rates were lower in the GtACH arm in the period 0-90 days. There were no other differences between arms in the secondary outcomes. Care home staff valued the training, systematic strategies and specialist peer support, but the incorporation of the GtACH programme documentation into routine care home practice was limited. No adverse events were recorded. The incremental cost was £20,889.42 per Dementia Specific Quality of Life-based quality-adjusted life-year and £4543.69 per quality-adjusted life-year based on the EuroQol-5 dimensions, five-level version. The mean number of falls was 1.889 (standard deviation 3.662) in the GtACH arm and 2.747 (standard deviation 7.414) in the control arm. Therefore, 0.858 falls were averted. The base-case incremental cost per fall averted was £190.62. CONCLUSION: The GtACH programme significantly reduced the falls rate in the study care homes without restricting residents' activity levels or increasing their dependency, and was cost-effective at current thresholds in the NHS. FUTURE WORK: Future work should include a broad implementation programme, focusing on scale and sustainability of the GtACH programme. LIMITATIONS: A key limitation was the fact that care home staff were not blinded, although risk was small because of the UK statutory requirement to record falls in care homes. TRIAL REGISTRATION: This trial is registered as ISRCTN34353836. 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. 26, No. 9. See the NIHR Journals Library website for further project information.

Falls in care home residents are common, unpleasant, costly and hard to prevent. We tested whether or not the Guide to Action for falls prevention in Care Homes (GtACH) programme was effective in preventing falls. In this programme, care home staff were systematically trained and supported in the assessment of residents' risk of falling and the generation of a falls reduction care plan. We undertook a randomised controlled trial comparing the GtACH programme with usual care, which does not involve this systematic attention to falls prevention. We also undertook a process evaluation, observing organisational and care processes, and an economic study to evaluate value for money. A total of 39 care homes were randomly allocated to the GtACH programme and 45 care homes were randomly allocated to usual care, involving a total of 1657 residents. The main comparison between the two arms was the rate of falls during months 4­6 after randomisation, when we expected any effect to be at its peak. We also assessed the falls rates before and 6 months after this period. We measured activity and dependency levels, as it was important to be sure that any reduction in the rate of falls was not achieved through restrictive care practices. We saw a 43% reduction in the falls rates of the GtACH programme participants during months 4­6, without observing any reduction in residents' activity or dependency. Care home staff and relatives were positive about the GtACH programme. The GtACH programme was good value for money, as it was likely to be cost-effective. The effect of the programme waned over months 6­12, which may be because some staff did not embed the GtACH programme in their usual practice routines, and awareness levels may have dropped.

Eczema Care Online behavioural interventions to support self-care for children and young people: two independent, pragmatic, randomised controlled trials.

OBJECTIVE: To determine the effectiveness of two online behavioural interventions, one for parents and carers and one for young people, to support eczema self-management. DESIGN: Two independent, pragmatic, parallel group, unmasked, randomised controlled trials. SETTING: 98 general practices in England. PARTICIPANTS: Parents and carers of children (0-12 years) with eczema (trial 1) and young people (13-25 years) with eczema (trial 2), excluding people with inactive or very mild eczema (≤5 on POEM, the Patient-Oriented Eczema Measure). INTERVENTIONS: Participants were randomised (1:1) using online software to receive usual eczema care or an online (www.EczemaCareOnline.org.uk) behavioural intervention for eczema plus usual care. MAIN OUTCOME MEASURES: Primary outcome was eczema symptoms rated using POEM (range 0-28, with 28 being very severe) every four weeks over 24 weeks. Outcomes were reported by parents or carers for children and by self-report for young people. Secondary outcomes included POEM score every four weeks over 52 weeks, quality of life, eczema control, itch intensity (young people only), patient enablement, treatment use, perceived barriers to treatment use, and intervention use. Analyses were carried out separately for the two trials and according to intention-to-treat principles. RESULTS: 340 parents or carers of children (169 usual care; 171 intervention) and 337 young people (169 usual care; 168 intervention) were randomised. The mean baseline POEM score was 12.8 (standard deviation 5.3) for parents and carers and 15.2 (5.4) for young people. Three young people withdrew from follow-up but did not withdraw their data. All randomised participants were included in the analyses. At 24 weeks, follow-up rates were 91.5% (311/340) for parents or carers and 90.2% (304/337) for young people. After controlling for baseline eczema severity and confounders, compared with usual care groups over 24 weeks, eczema severity improved in the intervention groups: mean difference in POEM score -1.5 (95% confidence interval -2.5 to -0.6; P=0.002) for parents or carers and -1.9 (-3.0 to -0.8; P<0.001) for young people. The number needed to treat to achieve a 2.5 difference in POEM score at 24 weeks was 6 in both trials. Improvements were sustained to 52 weeks in both trials. Enablement showed a statistically significant difference favouring the intervention group in both trials: adjusted mean difference at 24 weeks -0.7 (95% confidence interval -1.0 to -0.4) for parents or carers and -0.9 (-1.3 to -0.6) for young people. No harms were identified in either group. CONCLUSIONS: Two online interventions for self-management of eczema aimed at parents or carers of children with eczema and at young people with eczema provide a useful, sustained benefit in managing eczema severity in children and young people when offered in addition to usual eczema care. TRIAL REGISTRATION: ISRCTN registry ISRCTN79282252.

Multifactorial falls prevention programme compared with usual care in UK care homes for older people: multicentre cluster randomised controlled trial with economic evaluation.

OBJECTIVES: To determine the clinical and cost effectiveness of a multifactorial fall prevention programme compared with usual care in long term care homes. DESIGN: Multicentre, parallel, cluster randomised controlled trial. SETTING: Long term care homes in the UK, registered to care for older people or those with dementia. PARTICIPANTS: 1657 consenting residents and 84 care homes. 39 were randomised to the intervention group and 45 were randomised to usual care. INTERVENTIONS: Guide to Action for Care Homes (GtACH): a multifactorial fall prevention programme or usual care. MAIN OUTCOME MEASURES: Primary outcome measure was fall rate at 91-180 days after randomisation. The economic evaluation measured health related quality of life using quality adjusted life years (QALYs) derived from the five domain five level version of the EuroQoL index (EQ-5D-5L) or proxy version (EQ-5D-5L-P) and the Dementia Quality of Life utility measure (DEMQOL-U), which were self-completed by competent residents and by a care home staff member proxy (DEMQOL-P-U) for all residents (in case the ability to complete changed during the study) until 12 months after randomisation. Secondary outcome measures were falls at 1-90, 181-270, and 271-360 days after randomisation, Barthel index score, and the Physical Activity Measure-Residential Care Homes (PAM-RC) score at 91, 180, 270, and 360 days after randomisation. RESULTS: Mean age of residents was 85 years. 32% were men. GtACH training was delivered to 1051/1480 staff (71%). Primary outcome data were available for 630 participants in the GtACH group and 712 in the usual care group. The unadjusted incidence rate ratio for falls between 91 and 180 days was 0.57 (95% confidence interval 0.45 to 0.71, P<0.001) in favour of the GtACH programme (GtACH: six falls/1000 residents v usual care: 10 falls/1000). Barthel activities of daily living indices and PAM-RC scores were similar between groups at all time points. The incremental cost was £108 (95% confidence interval -£271.06 to 487.58), incremental QALYs gained for EQ-5D-5L-P was 0.024 (95% confidence interval 0.004 to 0.044) and for DEMQOL-P-U was 0.005 (-0.019 to 0.03). The incremental costs per EQ-5D-5L-P and DEMQOL-P-U based QALY were £4544 and £20 889, respectively. CONCLUSIONS: The GtACH programme was associated with a reduction in fall rate and cost effectiveness, without a decrease in activity or increase in dependency. TRIAL REGISTRATION: ISRCTN34353836.

Spironolactone for adult female acne (SAFA): protocol for a double-blind, placebo-controlled, phase III randomised study of spironolactone as systemic therapy for acne in adult women.

INTRODUCTION: Acne is one of the most common inflammatory skin diseases worldwide and can have significant psychosocial impact and cause permanent scarring. Spironolactone, a potassium-sparing diuretic, has antiandrogenic properties, potentially reducing sebum production and hyperkeratinisation in acne-prone follicles. Dermatologists have prescribed spironolactone for acne in women for over 30 years, but robust clinical study data are lacking. This study seeks to evaluate whether spironolactone is clinically effective and cost-effective in treating acne in women. METHODS AND ANALYSIS: Women (≥18 years) with persistent facial acne requiring systemic therapy are randomised to receive one tablet per day of 50 mg spironolactone or a matched placebo until week 6, increasing to up to two tablets per day (total of 100 mg spironolactone or matched placebo) until week 24, along with usual topical therapy if desired. Study treatment stops at week 24; participants are informed of their treatment allocation and enter an unblinded observational follow-up period for up to 6 months (up to week 52 after baseline). Primary outcome is the Acne-specific Quality of Life (Acne-QoL) symptom subscale score at week 12. Secondary outcomes include Acne-QoL total and subscales; participant acne self-assessment recorded on a 6-point Likert scale at 6, 12, 24 weeks and up to 52 weeks; Investigator's Global Assessment at weeks 6 and 12; cost and cost effectiveness are assessed over 24 weeks. Aiming to detect a group difference of 2 points on the Acne-QoL symptom subscale (SD 5.8, effect size 0.35), allowing for 20% loss to follow-up, gives a sample size of 398 participants. ETHICS AND DISSEMINATION: This protocol was approved by Wales Research Ethics Committee (18/WA/0420). Follow-up to be completed in early 2022. Findings will be disseminated to participants, peer-reviewed journals, networks and patient groups, on social media, on the study website and the Southampton Clinical Trials Unit website to maximise impact. TRIAL REGISTRATION NUMBER: ISRCTN12892056;Pre-results.

Content of Health Economics Analysis Plans (HEAPs) for Trial-Based Economic Evaluations: Expert Delphi Consensus Survey.

OBJECTIVES: Health economics analysis plans (HEAPs) currently lack consistency, with uncertainty surrounding appropriate content. We aimed to develop a list of essential items that should be included in HEAPs for economic evaluations conducted alongside randomized trials. METHODS: A list of potential items for inclusion was developed by examining existing HEAPs. An electronic Delphi survey was conducted among professional health economists. Respondents were asked to rate potential items from 1 (least important) to 9 (most important), suggest additional items, and comment on proposed items (round 1). A second survey (round 2) was emailed to participants, including the participant's own scores from round 1 along with summary results from the whole panel; participants were asked to rerate each item. Consensus criteria for inclusion in the final list were predefined as >70% of participants rating an item 7-9 and <15% rating it 1-3 after round 2. A final item selection meeting was held to scrutinize the results and adjudicate on items lacking consensus. RESULTS: 62 participants completed round 1 of the survey. The initial list included 72 potential items; all 72 were carried forward to round 2, and no new items were added. 48 round 1 respondents (77.4%) completed round 2 and reached consensus on 53 items. At the final meeting, the expert panel (n = 9) agreed that 58 items should be included in the essential list, moved 9 items to an optional list, and dropped 5 items. CONCLUSIONS: Via expert consensus opinion, this study identified 58 items that are considered essential in a HEAP.

Supporting self-care for eczema: protocol for two randomised controlled trials of ECO (Eczema Care Online) interventions for young people and parents/carers.

INTRODUCTION: Eczema care requires management of triggers and various treatments. We developed two online behavioural interventions to support eczema care called ECO (Eczema Care Online) for young people and ECO for families. This protocol describes two randomised controlled trials (RCTs) aimed to evaluate clinical and cost-effectiveness of the two interventions. METHODS AND ANALYSIS: Design: Two independent, pragmatic, unmasked, parallel group RCTs with internal pilots and nested health economic and process evaluation studies. Setting: Participants will be recruited from general practitioner practices in England. Participants: Young people aged 13-25 years with eczema and parents and carers of children aged 0-12 years with eczema, excluding inactive or very mild eczema (five or less on Patient-Oriented Eczema Measure (POEM)). Interventions: Participants will be randomised to online intervention plus usual care or to usual eczema care alone. Outcome measures: Primary outcome is eczema severity over 24 weeks measured by POEM. Secondary outcomes include POEM 4-weekly for 52 weeks, quality of life, eczema control, itch intensity (young people only), patient enablement, health service and treatment use. Process measures include treatment adherence, barriers to adherence and intervention usage. Our sample sizes of 303 participants per trial are powered to detect a group difference of 2.5 (SD 6.5) in monthly POEM scores over 24 weeks (significance 0.05, power 0.9), allowing for 20% loss to follow-up. Cost-effectiveness analysis will be from a National Health Service and personal social service perspective. Qualitative and quantitative process evaluation will help understand the mechanisms of action and participant experiences and inform implementation. ETHICS AND DISSEMINATION: The study has been approved by South Central Oxford A Research Ethics Committee (19/SC/0351). Recruitment is ongoing, and follow-up will be completed by mid-2022. Findings will be disseminated to participants, the public, dermatology and primary care journals, and policy makers. TRIAL REGISTRATION NUMBER: ISRCTN79282252.

An individually randomised controlled multi-centre pragmatic trial with embedded economic and process evaluations of early vocational rehabilitation compared with usual care for stroke survivors: study protocol for the RETurn to work After stroKE (RETAKE) trial.

BACKGROUND: Return to work (RTW) is achieved by less than 50% of stroke survivors. The rising incidence of stroke among younger people, the UK economic forecast, and clinical drivers highlight the need for stroke survivors to receive support with RTW. However, evidence for this type of support is lacking. This randomised controlled trial (RCT) will investigate whether Early Stroke Specialist Vocational Rehabilitation (ESSVR) plus usual care (UC) (i.e. usual NHS rehabilitation) is more clinically and cost-effective for supporting post-stroke RTW, than UC alone. METHODS: Seven hundred sixty stroke survivors and their carers will be recruited from approximately 20 NHS stroke services. A 5:4 allocation ratio will be employed to randomise participants to receive ESSVR plus UC, or UC alone. The individually tailored ESSVR intervention will commence within 12 weeks of stroke onset and be delivered for up to 12 months as necessary by trained RETAKE occupational therapists in the community, participants' homes or workplaces, and outpatient/inpatient therapy settings, via telephone, email, or SMS text message. Outcome data will be collected via self-report questionnaires administered by post or online at 3, 6, and 12 months follow-up. The primary outcome will be self-reported RTW and job retention at 12 months (minimum 2 h/week). Secondary outcomes will include mood, function, participation, health-related quality of life, confidence, intervention compliance, health and social care resource use, and mortality. An embedded economic evaluation will estimate cost-effectiveness and cost-utility analyses from National Health Service (NHS) and Personal Social Services (PSS) perspectives. An embedded process evaluation will employ a mixed methods approach to explore ESSVR implementation, contextual factors linked to outcome variation, and factors affecting NHS roll-out. DISCUSSION: This article describes the protocol for a multi-centre RCT evaluating the clinical- and cost-effectiveness of an early vocational rehabilitation intervention aimed at supporting adults to return to work following a stroke. Evidence favouring the ESSVR intervention would support its roll-out in NHS settings. TRIAL REGISTRATION: ISRCTN, ISRCTN12464275 . Registered on 26 February 2018.