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

Article history

The research reported in this issue of the journal was funded by the HTA programme as award number 12/67/12. The contractual start date was in June 2014. The draft manuscript began editorial review in September 2022 and was accepted for publication in May 2023. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The HTA editors and publisher have tried to ensure the accuracy of the authors’ manuscript and would like to thank the reviewers for their constructive comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this article.

Copyright statement

Copyright © 2024 Bradshaw et al. This work was produced by Bradshaw et al. under the terms of a commissioning contract issued by the Secretary of State for Health and Social Care. This is an Open Access publication distributed under the terms of the Creative Commons Attribution CC BY 4.0 licence, which permits unrestricted use, distribution, reproduction and adaptation in any medium and for any purpose provided that it is properly attributed. See: https://creativecommons.org/licenses/by/4.0/. For attribution the title, original author(s), the publication source – NIHR Journals Library, and the DOI of the publication must be cited.

2024 Bradshaw et al.

Background

Terminology and disease definition: In this monograph, we use the term ‘eczema’ throughout as a term commonly used in the UK to denote atopic eczema (AE) [also known as atopic dermatitis (AD) in the USA and other countries]. It could be argued that using the term ‘eczema’ is more precise, as around 50% of cases of ‘atopic’ eczema are not atopic2 [defined as immunoglobulin E (IgE) sensitivity to common environmental allergens determined by skin prick or blood tests]. The term ‘eczema’ is also the preferred term designated by the World Allergy Organization nomenclature committee. 3 A long list of major and minor clinical diagnostic criteria for eczema were suggested by Hanifin and Rajka in 1980 which were later refined in 1994 into a minimum list of reliable discriminators by a UK diagnostic criteria working party led by one of the authors (HW)4 (Table 1).

The UK diagnostic criteria have been used for this study and are supplemented by a detailed training manual for users. 5

Defining a new/incident case of eczema for use in prospective studies has been challenging as most definitions rightly include an element of chronicity,6 which is important to separate true eczema from many unclassified transient irritant forms of dermatitis in early life. 7 A 1-year period prevalence is used in the UK diagnostic criteria to capture chronicity and overcome seasonal variation.

What is eczema? Eczema is a chronic inflammatory skin condition characterised by symptoms of itching, stinging and burning of the skin. Itching can lead to sleep loss, poor concentration and a reduction in quality of life. Eczema can affect any part of the body. Secondary infection of the skin with bacteria (most commonly Staphylococcus aureus) is common. Involvement of the cheeks and outer limbs and trunk is common in infancy, whereas in the older child, involvement of the skin creases such as behind the knees and elbow folds is common. The skin is inflamed, appearing red in lighter skin tones and a dark purple or brown colour in dark skin. Chronic scratching leads to leathery thickening of the skin (termed lichenification).

Eczema is caused by a combination of genetic and environmental factors. Genes controlling skin barrier formation and inflammatory responses are important. Epidemiological studies indicate that environmental factors are also critical for determining disease expression: eczema has increased in prevalence over the last 30 years; people migrating from low- to high-prevalence countries develop similarly high rates in the adopted country; and eczema prevalence increases with small family size and higher socioeconomic group. 8–10 Increased sensitivity to food and environmental allergens such as house dust mite is common in eczema. The role of gut and skin microbiota in driving eczema remains controversial. 11 Most cases of childhood eczema improve in childhood but around 5% persist into adulthood. 12 Although eczema is still considered as one disease for the purpose of scientific studies and clinical trials, recent studies suggest that it is composed of several distinct sub-phenotypes or endotypes with different disease trajectories. 13 The relationship between skin barrier dysfunction and underlying upregulation of type-2-mediated immune responses is summarised elsewhere. 14

Asthma, hay fever and food allergy (collectively called ‘atopic’ disorders) are also commoner in children with eczema and perhaps best considered as comorbidities rather than conditions that inevitably progress in the same individuals as part of the so-called allergic march (Figure 1). 16 Some children with eczema are also allergic to foods such as egg and nuts. Current thinking is that eczema in early life leads to food allergy rather than the other way around.

FIGURE 1.

Illustration of the typical onset of symptoms of allergic diseases during childhood. Reprinted from Davidsonet al. (2019),15 Copyright (2023), with permission from Elsevier.

Eczema affects around 20% of children worldwide17 and around 5–10% of adults. 18 Black children in the UK seem to have an increased prevalence of eczema, the reasons for which are unclear. 19 Although around two-thirds of cases of childhood eczema are mild,20 moderate to severe eczema (Figure 2) can result in a significant quality-of-life impairment. 21 Having eczema or a child with eczema also confers high direct and indirect financial costs. 22

FIGURE 2.

Severe eczema is associated with poor quality of life in children.

Treatment of eczema. These are best summarised in the National Institute for Health and Care Excellence (NICE) eczema clinical knowledge summary. 23 Treatment depends to a large extent on eczema severity. In clinical practice, severity is commonly assessed using the Patient-Oriented Eczema Measure (POEM) which records eczema symptoms over the last week. 24 Mild eczema corresponds to a POEM score of 0–7, moderate 8–16 and severe/very severe ranging from 17 to 28. 25 In addition to avoiding irritants such as soap and rough clothing, mild eczema is generally treated in the community with topical application of creams and ointments such as short bursts of mild potency topical corticosteroids for inflammatory flares and emollients for restoring the skin barrier, flare prevention and treatment of dry skin symptoms. Moderate disease requires more potent topical corticosteroids and/or the addition of topical calcineurin inhibitors such as tacrolimus and pimecrolimus, often used proactively on weekends to prevent flares. More severe eczema requires specialist input and may require third-line treatments such as ultraviolet light or systemic immunomodulatory therapy such as ciclosporin, methotrexate or biologics such as dupilumab and baricitinib. 26 Three more biologics (abrocitinib and upadacitinib – both JAK1 inhibitors, and tralokinumab – a human monoclonal antibody that inhibits interleukin-13) have recently been approved by NICE for severe eczema27 and a large range of biologics are currently in development. There is a considerable unmet need for eczema care in the UK, with most treatment carried out at home with little contact with healthcare professionals. 14 Self-care informed by theory-based, evidence-informed online educational programmes have been shown to result in sustained benefit for managing eczema severity. 28

While good progress has been made with new topical and systemic treatments for established eczema,29 relatively little attention has been paid to the prevention of eczema – arguably a more desirable approach than the daily lifetime toil of applying greasy ointments or requiring expensive medicine that modify the body’s immune system in individuals in whom a long chain of pathological events have already occurred (Figure 3). 31

FIGURE 3.

Upstream prevention of eczema is a more desirable aim than treating sick individuals with costly drugs who present after a long chain of multistage events.

Rationale for the barrier enhancement for eczema prevention trial

A summary of the approaches that have been used to try and prevent eczema and the methodological considerations for such preventive studies have been summarised elsewhere. 32 In brief, systematic reviews of prevention strategies covering exclusive and prolonged breastfeeding, or those targeting reduction in food and/or airborne allergens in pregnancy and/or shortly after birth have not shown clear benefit. Maternal/infant supplements of vitamin D has also not shown any benefit. Some evidence supports the role of probiotics to prevent eczema, but the studies are quite variable and might benefit from individual patient data meta-analysis.

Interest in the use of emollients for preventing or reducing the severity of childhood eczema has been around for many years and was suggested by one of the authors (HW) at the 2001 International Symposium of Atopic Dermatitis in Portland. Although the idea gained some traction as it was already known that dry skin preceded the development of visible eczema, it was the discovery that mutations in the gene encoding filaggrin (FLG), a key skin barrier protein, that accelerated interest in emollients as a potential intervention for preventing eczema. 33 FLG mutations have since been shown to represent the strongest and most consistent genetic risk factor for eczema. Later studies showed that FLG-null mutations were also associated with related atopic conditions including asthma, hay fever and peanut allergy. 34 Intense interest grew in the concept of skin barrier dysfunction as the initial step in eczema development. In addition to FLG mutations, skin barrier defects are thought to arise as a result of immune dysregulation, low levels of antimicrobial peptides, a general disruption in skin flora (dysbiosis). 35 The genetic predisposition to skin barrier impairment led to the idea that babies at high risk of developing eczema are born with a skin barrier that allows irritants and allergens to initiate skin inflammation and hence set up a cascade of inflammatory events that could lead to chronic eczema driven by autoimmune mechanisms as a result of chronic scratching. 36

Emollients are used to improve the barrier function of skin by providing lipids to the outermost stratum corneum and by trapping water which in turn improves skin hydration. Emollients may prevent inflammation caused by external irritants as they are used to prevent irritant occupational hand eczema. 37 Emollients had also been shown to reduce skin inflammation in premature babies38 as well as preventing eczema flares in those with established eczema. 39 An earlier open-label pilot study of emollient therapy from birth showed that only 15% of high-risk infants developed eczema against an expected rate of 30–50%. 40 A case-control study conducted in Kenya published in 1991 also suggested that petroleum had protective effect against the development of eczema. 41

A workstream within a NIHR-funded programme grant conducted by several authors focused on exploring the feasibility of conducting a national trial of emollients to prevent eczema. At the time, there was considerable uncertainty of whether families with a strong history of atopic disease (eczema, asthma, hay fever) would agree to be randomised to normal care or daily application of an emollient to their newborn child. A series of pilot studies including qualitative work with families was carried out to explore emollient preferences. Full details of the pilot studies are described in the Programme Grant for Applied Research report. 42 Since some emollients such as aqueous cream had been shown to paradoxically damage the skin barrier,43 a mechanistic study by experts in skin barrier science was done to show that the two preferred emollients did not cause any such skin barrier disruption. 44 A feasibility randomised controlled trial (RCT) of 124 families was conducted and showed that the intervention was acceptable and that it was possible to conduct a national clinical trial. Although not powered to detect a difference in eczema prevention, infants in the emollient group in the feasibility study showed a reduced risk of developing eczema at 6 months of age compared to controls [22% vs. 43%, respectively, relative risk (RR) 0.50, 95% confidence interval (CI) 0.28 to 0.90; p-value = 0.017]. 42 Another small trial of 118 infants in Japan showed similar results, with 32% fewer neonates who received moisturiser developing eczema by week 32 when compared with control infants. 45

On the basis of the need to prevent eczema, empirical evidence on the role of a defective skin barrier as the initial event in eczema development, growing signals from observational and randomised pilot studies, a strong case was therefore made to the NIHR Health Technology Assessment Programme to fund a national trial of emollients to prevent eczema in babies at high risk of developing the condition. Timing was important as interest in the potential for emollients to prevent eczema was now becoming an entrenched belief following the two small pilot studies, and parents with a strong family history of atopic disease across the world were beginning to use emollients to prevent eczema in their newborns. Commercial companies were responding to demand by developing ‘designer’ emollients to enhance the skin barrier. The window of public/patient and healthcare professional equipoise was limited.

We therefore sought to test the hypothesis whether daily emollient application for 12 months after birth can reduce the development of eczema.

Trial objectives

Trial design and setting

This was a randomised, controlled, two-arm (skin-care advice plus emollient vs. skin-care advice alone), parallel group, multicentre, assessor blind trial with 5-year follow-up and primary outcome assessed at 2 years (Figure 4). Recruitment took place in 12 secondary care sites and four primary care sites in England (see Appendix 1, Figure 12).

FIGURE 4.

Schematic diagram showing the trial design and duration for participating families. a, Screening took place during pregnancy or within 21 days of delivery. Reproduced from Chalmers et al. 46 under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/).

A methodological two-by-two factorial substudy was also nested within the trial to investigate the effectiveness of two interventions on the rates of follow-up data collection. The interventions were: (1) short message service (SMS) notification prior to sending questionnaires at 3, 6, 12 and 18 months versus no SMS notification and (2) sending the £10 voucher for the primary follow-up visit at 24 months with the invitation letter versus giving the voucher at the visit. Full details can be found in the studies within a trial (SWAT) registry (SWAT Repository Store ID 25). 48

Participants and eligibility

The eligibility criteria for the participants are shown below.

Outcomes

Full details of definitions and derivation of outcomes are given in the statistical analysis plan (SAP). 47

Randomisation and blinding

Within 21 days of the birth of the baby, a baseline visit was conducted (either on the phone, via e-mail or face to face) with the research nurse to confirm eligibility and collect baseline data. Babies meeting the eligibility criteria were then randomised by the research nurse via a web-based randomisation system developed and maintained by Nottingham Clinical Trials Unit (NCTU).

The randomisation schedule was based on a computer-generated pseudo-random code using random permuted blocks of randomly varying size created by NCTU and held on a secure University of Nottingham server. Infants were allocated in a 1 : 1 ratio to either emollient and standard skin-care advice (intervention group) or standard skin-care advice only (control group). Randomisation was stratified by recruiting centre and number of immediate family members (parents/siblings) with atopic disease (one, two, or more than two family members with either eczema, asthma or hay fever).

Parents were informed of their child’s allocation by staff at NCTU by letter. While it was not possible to blind parents to the treatment allocation, efforts were made to minimise expectation bias by emphasising that information on the effect of emollient in addition to standard skin-care advice was limited.

Research nurses were not informed of the allocation to maintain blinding for the follow-up visit for the primary outcome at 2 years. To reduce the chance of the research nurse being unblinded by the parents at the 2-year visit prior to the skin examination for eczema, the appointment letter reminded parents not to tell the nurse which group they had been assigned to in the first year and skin assessments were conducted first during the visit.

Researchers involved in the food allergy assessment process were also blinded to treatment allocation.

The trial statisticians and health economists remained blinded to treatment allocation until after the initial database lock for the analysis of primary outcome data at 2 years.

Interventions

Trial assessments and procedures

Parents were initially contacted by telephone by the NCTU approximately 2 weeks after randomisation to check they have received their skin-care advice pack and web link for the video, and for infants randomised to the intervention group, to check the date that the family started applying the emollient. Parents were also reminded to contact the NCTU if they had any questions or problems (to protect the research nurses from becoming unblinded).

Parents were asked to complete web-based questionnaires at 3, 6, 12, 18, 36, 48 and 60 months to collect information on any skin problems, eczema and other allergy symptoms (including diagnosis, prescriptions and health resource use), feeding, skin-care practices (including emollient use during the intervention period), skin infections, infant slippage incidents within an hour of applying skin-care products, reactions to food and quality of life as detailed in Table 2 (all questionnaires available at47). Reminders were sent by e-mail after 2 and 3 weeks of non-completion and the questionnaires could be completed up to 4 weeks after the initial e-mail invitation was sent. Paper copies of the questionnaire were sent by post (with pre-paid envelopes) if parents did not wish to complete the questionnaires online. From May 2016, staff at the NCTU also telephoned and/or sent a text message to participants who had not completed the questionnaire after the first reminder and gave participants the opportunity to complete the questionnaire on the phone.

At 24 months, a face-to-face visit with a research nurse took place either in the family home or in clinic according to parent preference. Prior to the first appointment, 28 research nurses were trained in all assessments either by attending an in-person training day or by watching a series of training videos. This included training in diagnosing eczema using the UK diagnostic criteria, the EASI, skin prick test (SPT) and anaphylaxis. After this initial training, nurses used the UKWP Diagnostic Criteria and performed an EASI assessment in clinic with three patients with the local Principal Investigator. Specialist allergy nurses accompanied research nurses at their initial 24 months visits to sign off on proficiency in SPT competency and using an EpiPen (Viatris UK HealthCare Ltd., Potters Bar, Hertfordshire, UK, for anaphylaxis).

After arranging the 24-month visit, the research nurse sent parents an information leaflet and sheet to explain that their child would be offered an allergy test (SPT) at the visit. The nurse then discussed the SPT during the visit and took consent for this if the parents were willing for the child to have the optional allergy test.

During the visit, the research nurse conducted the skin examination for the UKWP Criteria and the EASI and for parents who had given the additional optional consents, collected a saliva sample and conducted a SPT. Parents were also asked to complete the POEM, EQ-5D and CHU-9D questionnaires and another questionnaire to collect information about skin problems, reactions to food, symptoms of allergic rhinitis and wheezing, skin care/washing and other characteristics potentially associated with the development of eczema (e.g. antibiotic use since birth, furry pets, dust mite reduction measures, number of other children in the household and whether the child attends nursery or playgroup), as detailed in Table 2 (case report form for 24-month visit available at NIHR Funding and Awards47). At the end of the visit, nurses recorded if they had become aware of which group the child had been randomised to and if so whether this happened before, during or after the skin examination.

Skin prick testing was carried out following a trial-specific procedure in line with the British Society for Allergy and Clinical Immunology procedures for SPT55 (Appendix 2 of protocol v7.0 26 February 2021, see NIHR Funding and Awards47). The following allergens were tested; grass pollen mix, dust mite and cat (Allergopharma GmBH & Co., Reinbek, Schleswig-Holstein, Germany), peanut (Inmunotek, Madrid, Spain), fresh skimmed cow’s milk and fresh chicken egg. Positive (1% histamine) and negative (0.9% saline) controls were used (Allergopharma GmBH & Co.). The research nurse measured the size of the reactions, and the results were reviewed by the BEEP food allergy team.

If it was not possible to complete a face-to-face visit, data collection was attempted remotely by telephone, text, e-mail or post. If no follow-up with the family was possible at 24 months, the NCTU attempted to collect key minimal data around diagnoses of eczema and food allergy (including number of prescriptions, primary and secondary care visits) from the child’s GP.

Children with a positive SPT or history suggestive of food allergy, where further information was needed to confirm a food allergy, were invited for a supervised oral food challenge (Figure 5) in an allergy clinic at Imperial College Healthcare National Health Service (NHS) Trust or Sheffield Children’s Hospital NHS Trust. A trial-specific food challenge information sheet was sent to parents of children invited to the food challenge and if needed the food allergy team contacted parents to gather more information about the child’s food allergy history. Parents who agreed to take part gave consent for their child to have a food challenge to confirm whether their child had a food allergy. Oral food challenges were conducted by experienced allergy nurses blinded to treatment allocation following a trial-specific standard procedure using incremental doses or a single dose of the relevant food (see Appendix 3 of protocol v7.0 26 February 2021, see NIHR Funding and Awards47). Allergy nurses were able to review SPT results and allergy history as needed to inform clinical decision-making. Trained nurses supported by a consultant paediatric allergist evaluated whether there had been a clinical reaction to the food using modified practical allergy (PRACTALL) and Integrated Approaches to Food Allergen and Allergy Risk Management criteria. 57,58 Clinical reactions during the food challenge were treated using standard clinical guidelines, with antihistamine, bronchodilator, intramuscular adrenaline or other medications, as needed.

FIGURE 5.

Food allergy assessment process.

For participants invited to a food challenge where this did not take place, a panel of experienced paediatric allergists agreed allergy status (see Figure 5). The panel developed and validated an algorithm to make the food allergy diagnosis. 59 The panel were blinded to treatment allocation and used all available information from the questionnaires and assessments and, where necessary, from secondary care records and direct communication with participants’ parents. Following the SPT and food challenge (where applicable), parents and the child’s GP were sent a letter summarising the findings and any recommended action by the BEEP food allergy team.

Saliva samples were sent to the Centre for Dermatology and Genetic Medicine at the University of Dundee for deoxyribonucleic acid (DNA) extraction by standard techniques. DNA samples were genotyped for the four most common FLG null mutations in the white European population (2282del4, R501X, S3247X and R2447X). 60

Small tokens of appreciation were sent to all participating families by the NCTU throughout the trial including BEEP branded muslin or bib at randomisation, birthday card and BEEP branded plastic cutlery set or storybook at the child’s first birthday and BEEP branded cloth shoulder bag sent at 18 months. At 24 months parents received a £10 voucher either with the invitation letter for the primary follow-up visit or at the visit according to their allocation for the nested SWAT. A £10 voucher was also sent to parents on completion of the 48- and 60-month questionnaire. Parents were also sent trial newsletters every 6 months (from January 2016). The newsletter sent to parents in February 2020 summarised the results for the primary and secondary outcomes up to 24 months. 61

Trial oversight

An independent Trial Steering Committee (TSC) provided overall supervision of the trial. The TSC had an independent chair and four independent members (parent representative, statistician, consultant dermatologist and paediatric epidemiologist as detailed in Acknowledgements). The TSC met at least once a year during recruitment and follow-up for the primary outcome.

Due to the very low medical risk associated with the intervention, there was no separate data monitoring committee for the trial. Safety outcomes were monitored by the TSC during closed sessions of the meetings attended by only the independent members.

Sample size

The sample size was based on assuming 30% of children in the control group would have eczema between 1 and 2 years of age (based on previous epidemiological studies in this high-risk population) and a conservative relative reduction of 30% in the intervention group. This relative reduction was considered conservative as in the pilot study, a 50% reduction in eczema at 6 months was observed [43% developed eczema in the control group (n = 55) and 22% developed eczema in the emollient group (n = 53), 95% CI for RR 0.28 to 0.90]. The anticipated effect size was lower in the main trial due to the more pragmatic study design and the longer-term outcome assessment; however, such a reduction would still have important implications for families and health services.

A total of 1282 children were required to allow this difference to be detected (i.e. 30% of children in the control group, 30% relative reduction to –21% of children in the intervention group) at the 5% significance level (two-sided) with 90% power and allowing for 20% attrition at 24 months.

The protocol specified that the assumptions underpinning the sample size would be checked by independent members of the TSC after approximately 21 months of recruitment (i.e. by checking the percentage of children with eczema in the control group and percentage with follow-up data). However, the original target sample size of 1282 was exceeded prior to this point and the Chief Investigator requested that the sample size review therefore be brought forwards. At this point (July 2016), sites were told to stop consenting women to the trial however randomisation continued for women who consented before this date prior to the birth of their baby. In August 2016, independent members of the TSC were sent details of the follow-up questionnaire completion rate in each group and parental-reported medical diagnosis of eczema in the control group from the questionnaires by a NCTU statistician independent of BEEP. The TSC were asked to advise on whether consent and randomisation should continue. The TSC recommended that consent to the trial should be permanently terminated but randomisation should continue for any women who had consented but had not yet been randomised. The total number of children randomised was expected to be approximately 1400.

Stopping rules and discontinuation

There was no planned interim analysis of treatment efficacy for the primary outcomes. The criteria below (Box 1) were specified in the protocol in relation to recruitment and adherence to trigger discussion with the TSC and funder regarding the best course of action.

Statistical methods

Analyses are detailed in the SAP. Version 1.0 of the SAP was finalised prior to database lock and release of treatment allocation codes for analysis of the primary and secondary outcomes at 24 months. 47 Version 2.0 of the SAP was finalised prior to the database lock for the analysis of the tertiary outcomes at 60 months. 47 All analyses were carried out using Stata 15.0 or above (StataCorp LP, College Station, TX, USA), unless otherwise specified.

The main approach for analysis was to analyse participants (children) as randomised regardless of adherence with the allocated intervention using available data (i.e. without imputation for missing data) with sensitivity analysis for key outcomes using multiple imputation for missing data. Estimates of the intervention effect are presented with 95% CIs.

Summary of changes to the protocol

A full list of all substantial amendments to the protocol can be found in Appendix 2. All amendments were reviewed by the Sponsor before submission to, and approval by, the Research Ethics Committee and/or the Health Research Authority.

Patient and public involvement

Patient and public involvement (PPI) members of the team provided a vital and valuable role throughout the trial. The aim of PPI was to enhance the design of the main trial.

We were fortunate in being able to conduct a thorough pilot trial as part of a programme grant42 in preparation for this definitive trial. The pilot RCT was similar in design to the main trial and therefore provided the opportunity for meaningful and significant input from parents who had direct experience of a similar eczema prevention trial. Their opinions and feedback during the design of the main trial were therefore largely based on experience rather than hypothetical scenarios and were key in reaching the final design of this main trial. The main areas of input from parents who had participated in the pilot were around the following issues:

1. Continue applying emollient until the child was 12 months old rather than the 6 months tested in the pilot. Parental feedback strongly suggested was that this was acceptable, and in fact, many had chosen to do so anyway in the pilot. Therefore, we felt confident that an extended intervention period of 12 months could be introduced to the main trial without high risk to intervention adherence and this was reflected in the continued high adherence rates during months 6–12 of the intervention period.

2. Restricting choice of emollient to cream/gel formulation only. Parents reported in the pilot that they liked having a choice of emollient, so it was important to retain this. However, because the cream/gel formulation was the most popular, the decision was made to offer a choice from within this emollient type. A group of parents who had participated in the pilot trial participated in a preference study which, along with mechanistic studies, supported the choice of emollient for the main trial.

3. Number of visits reduced to only screening and 24-month follow-up. The pilot trial involved multiple visits to the nurse to check the skin for signs of eczema. The feedback from parents was that although they appreciated the support, they often felt the visits were not necessary, especially when there was nothing wrong with their child’s skin. Taking this parental feedback into account and to design a large definitive trial that was more practical to deliver, the interim follow-up was conducted via online questionnaires and via contact with the co-ordinating centre over the telephone, coupled with advice to visit the GP if they had concerns about their child’s skin. This was a successful approach in terms of making it a viable trial but contacting the higher proportion of non-completers of online questionnaires than anticipated required more resource from the co-ordinating centre. Incentives to complete the questionnaires were introduced part way through the trial to help with completion rates.

4. Addition of allergic sensitisation (skin prick) tests at the 24-month visit. As these tests were not done as part of the pilot trial it was essential to get input from parents into the acceptability of these in the main trial. Parents were generally very keen for their child to receive these tests, but due to funding restrictions, SPTs were introduced part way through the trial recruitment period. As a result, and because of additional concerns raised by families participating in the main trial about the need to travel to the oral food challenge, the SPTs were introduced as optional and separate consent was sought.

Further details of how parental input shaped the main trial design are in the pilot study report. 42

In the early stages of the trial set-up, the Centre of Evidence Based Dermatology (CEBD) patient panel also provided input. The panel comprises of people with lived experience of a wide range of skin diseases but the input into this trial was sought mainly from members who are parents of children with eczema along with some adults with eczema. The panel reviewed and improved the BEEP patient-facing study documentation, including the participant information sheet (PIS), consent forms and the design and content of the online follow-up questionnaires. These were refined as a result of the feedback to ensure they were suitable. As the main trial progressed through the pilot phase, further feedback was sought from both parents and an eczema support group.

Patient and public involvement representatives were involved in promoting and publicising the trial (through local television and radio) alongside the Chief Investigator. In addition, the PPI team were consulted to help modify documentation to increase up-take of the SPT at the 24-month visit and subsequent food challenges. Their advice was sought to help disseminate the important primary outcome findings. We also decided to share the 2-year primary outcome results directly with participating families61 as our first audience, that is before the main publication in The Lancet. Additional PPI colleagues with lived experience of eczema also participated in our 5-year results reveal meeting and were helpful in contextualising the key results on lack of benefit and possible signals of increased minor skin infections and skin sensitisation.

A PPI representative sat on the TSC and attended the meetings throughout the trial and provided key advice on how to balance the key messages for parents and carers.

Recruitment

Recruitment to the trial took place between 19 November 2014 and 14 July 2016 and the last baby was randomised on 18 November 2016. During this time, 4963 families were assessed for eligibility, and of these 1484 families consented (30%) (Figure 6). The main reason families assessed for eligibility did not consent was due to declining (41% of those assessed). After the baby was born, 1395 babies were randomised (94%). Non-randomisation after consent was mainly as a result of no longer being eligible (n = 50), mostly as babies were born preterm (n = 41). One baby was randomly assigned in error 62 days after birth so was not included further. Of the 1394 babies, 693 were randomised to the emollient group and 701 to the control group (randomisation by site presented in Appendix 3, Table 28). The mean number of days between birth and randomisation was 5.8 [standard deviation (SD) 5.7]. Four babies were randomised more than 21 days after they were born.

FIGURE 6.

Participant flow diagram to 24 months. a, Insufficient data collected to derive primary outcome for two participants (one in each group) at 24 months.

Baseline characteristics

Family and baseline baby characteristics were well balanced across groups (Table 4). The mean age of the mothers at randomisation was 31 (SD 5.3), 32% of babies were delivered by caesarean section and 82% of babies had at least one first-degree relative with a history of eczema (parent report of doctor diagnosis).

Follow-up to 24 months

Follow-up of the infants between 3 and 24 months took place between February 2015 and November 2018. The questionnaires at 3, 6, 12 and 18 months were completed for around 75% at each time point and completion was similar in both groups (Table 5). No questionnaires were completed for 14% of participants in both groups (see Table 5).

At 24 months, follow-up was completed for 1212 randomised participants (87%, Figure 6) and completion was similar in both groups. Most visits (1123 in total) were completed face to face with a research nurse. For 89 participants, where a face-to-face visit was not possible, some data were collected via telephone, e-mail, SMS or post, although for two participants insufficient data were collected to be able to derive the primary outcome. Research nurses completing the skin examination reported becoming aware of which group the child was randomised to (or possibly becoming aware) for 30 participants in the intervention group and 11 participants in the control group. For 12 participants in the intervention group and 6 in the control group, the research nurses reported that this unblinding happened before the examination of the child’s skin. Families of infants where no primary outcome data were collected in both groups were more likely to have joined the study after the birth of their baby rather than consenting antenatally, had slightly younger mothers on average when they were born and were more likely to be in a household with other children (see Appendix 3, Table 31). A slightly greater proportion of girls had primary outcome data collected compared to boys in the intervention group with the opposite observed in the control group (see Appendix 3, Table 31). The number of family members with a history of atopic disease, delivery method and days between birth and randomisation were similar between infants with and without primary outcome data collected (see Appendix 3, Table 31).

Of the 1212 infants where the 24-month follow-up visit was completed, SPTs to assess allergic sensitisation were fully completed for 81% in both groups (Table 6). Five children were given antihistamines after the SPT. No children had a serious allergic reaction to the SPTs requiring the use of an auto adrenaline injector.

Based on the results of the SPTs and/or parent report of consumption and reaction to milk, egg and peanut, 258 children were invited to a food challenge for at least one of the three foods with similar numbers invited in the two groups (see Table 6). At least one food challenge took place for 69 children (27%). Similar numbers in each group had food challenges for peanut and cow’s milk. Twice as many children in the intervention group had a food challenge for egg compared to the control group (24 vs. 11). There were no incidents of the person completing the food challenge becoming unblinded to the group that the child was randomised to. The main reason that food challenges were not conducted was due to parents being unwilling to participate or due to the travelling distance to the two centres where the food challenges were conducted. For allergy to each food, more than 75% of diagnoses were made by panel consensus due to food challenges not being conducted. For some of these children, the panel made a diagnosis of possible food allergy or food allergy unlikely where there was insufficient information available to make a more definitive diagnosis; these diagnoses were included in a sensitivity analysis for the main food allergy outcome (see Table 6).

Adherence with the allocated intervention

For families in the intervention group, 509 (73%) responded to the telephone call at around 2 weeks to check whether they had received the skin-care pack and emollients, and to collect information on the date they started applying the emollient to the infant. Of those responding, the median age that families reported starting to apply the emollient was 11 days after birth [interquartile range (IQR) 7–17], and 452 (89%) reported starting to apply the emollient within 3 weeks of birth.

In the year after randomisation, around half of families in the intervention group reported usually applying the emollient every day (Table 7) and emollient was applied at least 3 days per week by 75%. Most families reported usually applying the emollient to the arms/legs and trunk and around three-quarters also reported usually applying it to the face/neck. Emollient was most commonly applied once a day and most families reported usually applying the emollient after bathing or showering their child. The small number of parents who said that they had not used the emollient at all at each time point reported several different reasons for this (see Table 7).

Of families with complete data on emollient use at each time point, 88% at 3 months, 82% at 6 months and 74% at 12 months reported using the emollient at least 3 days per week over the majority of the child’s body (compliance, Table 7). Complete data on adherence over the first year were collected for 442 infants (64%) and of these 311 (70%) infants were considered fully compliant with the intervention (as defined in Table 3). Using the conservative assumptions described in the Statistical methods section for participants with missing questionnaires, full compliance over the first year in the intervention group was estimated to be 51% (350/693) (see Appendix 3, Table 33).

In the control group, self-directed use of emollients at least 3 days per week to most of the body (contamination) was reported for 18% (82/457), 17% (62/372) and 15% (49/324) at 3, 6 and 12 months, respectively, for infants who did not have a parental report of a doctor diagnosis of eczema (see Appendix 3, Table 32).

Washing, feeding and other post-randomisation characteristics between birth and 24 months

Parent report of washing practices at 6, 12 and 24 months in terms of frequency, the products used to wash the child and use of oils in the child’s bath water were balanced across the two groups (see Appendix 3, Table 34). Between 12 and 24 months, just under half of the families in the intervention group and just under 30% in the control group reported using a moisturiser on their child at least 3 days per week to most of the body. This moisturiser use was more common in both groups in children with a parental report of a clinical diagnosis of eczema (see Appendix 3, Table 35).

At 6 months, parental report of the milk type used to feed their baby since birth and the introduction of solid foods was similar in the two groups (see Appendix 3, Table 36). Around 40% of babies in both groups had antibiotics in their first year and 50% in their second year of life (see Appendix 3, Table 36). Other characteristics such as additional children in the household, use of dust mite reduction measures, water softeners fitted in the house and whether the child regularly attended nursery or a playgroup were also similar in both groups (see Appendix 3, Table 36).

By 24 months, almost all children had eaten foods containing cow’s milk and egg and over three-quarters had eaten foods containing peanut (see Appendix 3, Table 37). The timing of the introduction of these foods was similar in the two groups. The percentage of children who had consumed these three foods recently and frequently at 24 months was also similar in the two groups (see Appendix 3, Table 37).

Primary outcome: diagnosis of eczema between 12 and 24 months of age

Subgroup analysis

There was no evidence of an interaction effect with allocated group on the risk of eczema according to number of first-degree relatives with atopic disease, number of first-degree relatives with a history of eczema, FLG genotype, season of birth, water hardness or regular use of probiotics during pregnancy (see Figure 7, see also Appendix 3, Table 38).

FIGURE 7.

Adjusted RR with 95% CIs in each subgroup for primary outcome of diagnosis of eczema between 12 and 24 months.

Secondary outcomes

Eczema-related secondary outcomes

There were no differences between the groups in any of the secondary outcomes for eczema, including different definitions of eczema diagnosis (Table 9), time to onset of eczema (see Figure 8, Appendix 3, Figure 13 and Table 39) and severity of eczema (see Table 9, Figure 9 and Appendix 3, Table 40).

TABLE 9 - Secondary eczema outcomes

Questionnaire version, parents not asked questions on visible flexural dermatitis at 2 years.

Note

Results reproduced with permission from Chalmers et al. 1 (with some minor changes to wording and formatting). This is an Open Access article distributed in accordance with the terms of the Creative Commons Attrition (CC BY 4.0) licence, which permits others to distribute, remix, adapt and build on this work, for commercial use, provided the original work is properly cited. See https://creativecommons.org/licenses/by/4.0/.

Copyright © 2024 Bradshaw et al.

	Intervention	Control	Adjusted RR (95% CI)	Adjusted difference in risk (95% CI)
At 12 months
Eczema according to UKWP Diagnostic Criteria (parent completion)	103/516 (20%)	107/527 (20%)	0.98 (0.77 to 1.25)	−0.3% (−5.1% to 4.6%)
Moderate/severe/very severe on POEM	52/512 (10%)	49/522 (9%)	1.09 (0.75 to 1.57)	1.0% (−2.5% to 4.6%)
At 24 months
Presence of visible eczema at 24 months	151/555 (27%)	149/568 (26%)	1.05 (0.86 to 1.27)	1.1% (−4.0% to 6.3%)
Parent report of a clinical diagnosis of eczema between birth and 24 months	266/610 (44%)	282/616 (46%)	0.96 (0.85 to 1.08)	−2.0% (−7.5% to 3.6%)
Eczema according to UKWP Diagnostic Criteria (parent completiona)	187/599 (31%)	195/612 (32%)	0.98 (0.83 to 1.16)	−0.5% (−5.7% to 4.8%)
Moderate/severe/very severe eczema on EASI	9/553 (2%)	10/567 (2%)	0.93 (0.38 to 2.27)	0.0% (−1.5% to 1.4%)
Moderate/severe/very severe on POEM	58/576 (10%)	51/595 (9%)	1.18 (0.82 to 1.68)	1.7% (−1.6% to 5.0%)

FIGURE 8.

Time to onset of eczema based on first parental report of clinical diagnosis of eczema.

FIGURE 9.

Severity of eczema. (a) EASI at 24 months (blinded assessment of severity by research nurse) based on categories in Leshem et al. 56 (b) POEM at 12 months (parent-reported severity) based on categories in Charman et al 2013. (c) POEM at 24 months. Reproduced from Chalmers et al. 1 under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/).

Safety outcomes

Infant skin infections between birth and 12 months were reported by a slightly greater number of parents in the intervention group than in the control group: 89 in the intervention group (15%) and 67 parents in the control group (11%) with an incidence rate ratio of 1.55 (95% CI 1.15 to 2.09; Table 14). The types of skin infections reported by parents were diverse with impetigo and unspecified bacterial, viral or fungal skin infections the most common if known (see Table 14).

The number of parents reporting infant slippage incidents within an hour of applying skin-care products to the baby’s skin was small (n = 26, < 3%) and similar in both groups (see Table 14). The trial management team rang parents of children reporting a slippage incident on the questionnaires to find out more about what happened. Of the 20 parents who responded, all confirmed with the trial team that the baby was okay, and that the slippage incident had not caused a serious injury.

Tables showing reported skin infections and slippages according to allocated group and reported emollient use are shown in Appendix 3, Table 44.

Tertiary outcomes

Introduction

As described elsewhere in this report, the BEEP trial sought to determine if advising parents to apply an all-over-body application of emollient to their child’s skin throughout the first year of life in addition to standard infant skin-care advice might prevent the onset of eczema in children at high risk of allergic disease. The trial took a pragmatic, randomised, controlled, parallel group, multicentre assessor-blind design in which parents were advised to follow the skin-care advice for their child at home with minimal clinical contact. One thousand three hundred and ninety-four newborns at high risk of developing eczema were randomly allocated to the intervention or control arm. Standard practice infant skin-care advice was provided to all parents and those randomised to the intervention arm were also given advice to apply emollient daily to the child’s entire body surface area for the first year of the child’s life. Families were given a choice of two emollients (Doublebase Gel and Diprobase Cream). Diagnosis of eczema between 12 and 24 months of age (defined as meeting the UKWP Diagnostic criteria) was the primary outcome. The methods and results have been published1 showing no evidence that daily emollient during the first year of life prevents eczema in high-risk children and some evidence to suggest there may be an increased risk of skin infections.

Data on health resource use and quality of life were captured alongside the trial in order to undertake a within trial economic evaluation. Though concerns have been raised in the literature about so-called paradoxical (not clinically effective but yet found cost effective) conclusions between clinical and economic analyses of the same studies,68 we report the economic results despite the main clinical findings for several reasons. Firstly, the intervention was preventative in nature and when designing the study, we considered it may be possible for emollients not to be found statistically clinically effective yet estimated to be cost-effective. This is because the intervention is relatively cheap and thus even a small insignificant improvement across a lot of people could potentially be deemed cost-effective. Cost-effectiveness, via changes in resource use and costs, may also have been driven by improved secondary outcomes, such as change in severity of eczema, were such differences found. Secondly, Xu et al. 69 published a decision tree model estimating the cost-effectiveness of seven moisturisers used in the first 6 months of life to prevent eczema in high-risk individuals. The study concluded that daily moisturisation is a cost-effective preventative strategy that can reduce the burden of eczema. It is therefore important to report the economic evaluation for this preventative strategy based on individual-level data collected alongside the definitive trial in order to add to the evidence base around whether this preventative strategy is cost effective or not. Thirdly, since the data were collected, it is important to analyse and report it so as to help inform any future or related research that might find this analysis relevant. The current level of economic evidence available for interventions aimed at preventing and treating eczema is limited. 70,71 Understanding resource use, costs and quality of life in early life in high-risk children is of value in its own right and is something this study adds to the literature.

The primary objective of this within-trial economic evaluation was to estimate the cost-effectiveness of advice to provide daily all-over-body application of emollient during the first year of life for preventing AE in high-risk children over a 2-year time horizon. A sensitivity analysis is undertaken to estimate the medium-term cost-effectiveness at 5 years using a within-trial analysis.

Methods

Results

The full trial paper1 provides a detailed description of the final sample size and characteristics at 24 months. Of the 1394 babies randomly assigned to the emollient or control arm at the start of the study, 184 infants and their families either dropped out or were lost to follow-up by the 24-month period. This resulted in a sample of 1210 infants at 24 months: 598 allocated the emollient intervention alongside standard skin-care advice and 612 allocated standard skin-care advice only. Of these, 598 had complete cost and outcome data in the emollient intervention arm and 610 had this in the control arm (less than % missing) and it is this sample (n = 1208) that is analysed in the base-case CEA at 2 years.

Base-case cost-effectiveness analysis at 2 years

Table 25 presents the unadjusted and adjusted results of the CEA in terms of the number of eczema cases diagnosed together with an estimate of the ICER and separately the CEAC for the adjusted analysis (Figure 10). The incremental difference in cost for the emollient arm (n = 598) compared to the control arm (n = 610) was £87.45 (95% CI −54.31 to 229.27) (unadjusted this was £86.07, 95% CI £ −57.77 to 229.90). The adjusted incremental difference in proportion without eczema for the emollient arm compared with the control arm was 0.0164 (95% −0.0329 to 0.0656) (unadjusted was 0.012, 95% CI −0.0359 to 0.0600), meaning that the emollient arm had less cases (by a very small margin) of eczema at 24 months. The ICER was £5337 (£7281 unadjusted) per percentage decrease in risk of eczema. The amount decision-makers would be willing to pay per percentage decrease in risk of eczema is unknown, but it can be seen from the CEAC that there is a lot of uncertainty around the probability of the intervention being cost effective, at willingness-to -pay values over £10,000 per percentage decrease in risk of eczema the probability of cost-effectiveness is always < 60 to 72%.

TABLE 25 - Cost-effectiveness and CUA results at 2 years

CCA, complete-case analysis.

Analysis (N e, N c)	Incremental cost (UK£) (95% CI)	Incremental effect (95% CI)	ICER	% Cost effective at £20k (£30K)
CEA base case (CCA, unadjusted) (598, 610)	86.07 (−57.77 to 229.90)	0.012 (−0.0359 to 0.0600)	£7281 per percentage decrease in risk of eczema	Willingness-to-pay threshold per percentage decrease in risk of eczema unknown.
CEA base case (CCA, adjusted) (598, 610)	87.45 (−54.31 to 229.27)	0.0164 (−0.0329, 0.0656)	£5337 per percentage decrease in risk of eczema
CUA (CCA, CHU-9D, unadjusted) (524, 542)	81.47 (−80.21 to 243.14)	0.0010 (−0.0069 to 0.0089)	£82,250 per QALY	30% (36%)
CUA (CCA, CHU-9D, adjusted) (524, 542)	84.28 (−78.36 to 246.93)	0.0010 (−0.0068 to 0.0089)	£82,580 per QALY	29% (36%)

FIGURE 10.

Cost-effectiveness acceptability curve for the complete-case adjusted CEA analysis (UKWP-AD) at 2 years.

Secondary cost–utility analysis at 2 years

Proxy-reported Child Health Utility instrument-9 domains for the infant

The adjusted incremental difference in cost per infant for the emollient arm (n = 524) compared to the control arm (n = 542) was £82.28 (95% CI −78.36 to 246.93). The adjusted mean QALYs for infants was very slightly more in the emollient arm, incremental mean difference of 0.0010 (95% CI of −0.0068 to 0.0089), see Table 25. This means that the emollient arm was more expensive and slightly more effective than the control arm. The adjusted ICER was £82,580 which, when using a threshold value of £20,000 (£30,000), would not be considered cost-effective. 78 The probability of the intervention being cost-effective at 2 years was 29% (36%) for a threshold value of £20,000 (£30,000) (Figure 11).

FIGURE 11.

Cost-effectiveness acceptability curve for the complete-case adjusted CUA (CHU-9D) at 2 years.

EuroQol-5 Dimensions, five-level version for the main carer

The adjusted mean difference in the QALYs was close to zero, −0.0012 (95% CI −0.0308 to 0.0285) (see Table 24). We did not combine these results into a CUA as we only collected NHS resource use for the infants. However, on average main carers in the emollient arm had slightly lower QALYs than main carers in the control arm.

Discussion

Conclusions

The daily use of all-over-body application of emollient during the first year of life as described in this study is unlikely to be a cost-effective intervention in preventing AE in high-risk children under 2 years of age if a 2-year time horizon is taken. At 5 years the intervention appears to be cost-effective, but this seemed to reflect the high cost of inpatient hospital stays due to wheezing amongst a small proportion (< 4%) of the sample in a study that shows no clinical benefit for wheezing prevention at 5 years. The 5-year results in this study illustrate what Raftery et al. 68 call ‘doubly null’ results, that is no significant difference in both primary outcome and cost per patient. We seek to avoid ‘paradoxical’ conclusions at 5 years by exploring and acknowledging the issue (small incremental costs and effects) and factors (such as the differentially high wheezing inpatient costs between arms over years 3–5) that might explain the findings68 regarding not clinically effective but potentially cost-effective results. Resource allocation decisions should be based on the totality of evidence established by systematic reviews and meta-analysis. Our results add an important contribution to the evidence available to inform any future decisions in this clinical area. Our results also indicate that in terms of practicality it is possible to use the proxy CHU-9D with children as young as 2 years old and further research to explore the validity of this would be useful.

Main findings and interpretation

The overriding finding from BEEP is a lack of any clear benefit from emollients for the prevention of eczema in high-risk children. The findings are remarkably consistent across the range of eczema outcomes used and time points. Results for the main outcomes are robust to sensitivity analyses that account for missing data. In subgroup analysis, there was also no evidence of a difference in the effect of emollients on eczema prevention according to genetic risk of atopic disease, for example, presence of filaggrin gene mutations. No benefit was seen for eczema severity (which could still have been useful in terms of reducing health burden), time to onset of eczema or associated allergic diseases including food allergy, asthma or hay fever. While disappointing, the findings from this study are very important in that they indicate that perhaps skin barrier enhancement using emollients is not an effective pragmatic strategy to prevent eczema and associated diseases, despite earlier interest in this approach. The null result is important because it releases carers from the inconvenience and financial cost of daily emollient application.

Data beyond 2 years

The BEEP study is perhaps a little unusual in that the primary outcome for the 5 years study was elicited at 2 years. The original idea of the 5-year outcome was mainly to collect outcomes on other allergic diseases such as asthma that are potentially difficult to diagnose under the age of 5 years. We also sought to see whether any protective benefits of eczema prevention were transient or sustained as it is unclear from studies on probiotics to prevent eczema whether the benefits diminish over time. 96 The findings of no clinically useful eczema prevention at our primary outcome time point when study children were aged 2 years were upheld in parent-reported 3-, 4- and 5-year data of doctor-diagnosed eczema and other measures. We did not find any evidence of benefit for asthma or hay fever prevention, although we cannot exclude small degrees of benefit. We did not measure additional emollient-related safety outcomes beyond 2 years. None were reported spontaneously from participants for this period. Interestingly, moisturiser use over the body continued at a higher level in the intervention group than in the control group after the 12-month intervention period ceased. Such a ‘legacy’ effect might be due to routine or a genuine perceived benefit from parents, while some usage would have inevitably reflected the need to use emollients for recently diagnosed eczema.

Health economics

The economic evaluation results are consistent with the clinical findings of the study and finds that at 2 years the use of emollients to prevent eczema is unlikely to be cost-effective. The results at 5 years, if read uncritically, could be interpreted as suggesting the intervention is cost-effective over this longer period. However, incremental costs and effects were small in both the 2- and 5-year analyses. In addition, the costs in the 5-year analysis were largely driven by the small number of participants who incurred inpatient hospital costs due to wheezing and which were unequally distributed between the two study arms. Given the findings elsewhere in this report do not find evidence of benefit for asthma, or indeed hay fever, it seems unlikely these costs were related to the intervention. When they were excluded in a sensitivity analysis the CEA results suggest that the intervention is dominated by control (i.e. the intervention is both more costly and less effective than control).

Possible signals of harms?

Given that the combination of greasy emollients and water in the bathroom is a recipe for very slippery surfaces, one of our main concerns with the use of emollients was slippages. Thankfully, slippages were not common, and none were serious. More importantly, they were similar in intervention and control group and mainly due to non-study emollients for eczema or general skin-care use.

The finding of increased parental report of doctor-diagnosed skin infections in the intervention group is an area of concern. Although none were serious, they nevertheless represent a nuisance to the infant and parents and may involve healthcare contact. Interpretation of the skin infection data is challenging though as the range of skin infections was quite wide and not coherent with the sort of specific infections such as folliculitis due to S. aureus that one would normally associate with eczema or occlusion of the skin with emollients. 39 Although we recorded parental report of doctor-diagnosed skin infection, we did not verify these reports or diagnoses with the doctors concerned and whether such infections were confirmed by laboratory investigations. Ideally, more specific investigation of skin infections should be undertaken in ongoing and future emollient prevention studies.

Skin sensitisation and food allergy outcomes; although funded separately, the results of this aspect of the BEEP warrant some brief discussion as food allergy and eczema are so inextricably linked. 97 Our hope was that successful prevention or postponement, of eczema onset might lead to prevention of food allergy, since early-onset IgE-mediated food allergy is thought to be directly caused by early-onset eczema. 98 BEEP trial findings showed no prevention or postponement of eczema, and a possible increase in IgE-mediated food allergy. Food allergy is less common than eczema, so the trial was not adequately powered to detect changes in food allergy prevalence. This means there is significant uncertainty about food allergy outcomes. While most food allergy outcomes, including the a priori defined main food allergy outcome, showed increased food allergy or sensitisation in the intervention group, CIs were wide and, for most analyses, included the possibility of no effect. If emollient application increases risk of IgE-mediated food allergy, then this may be an important mediating factor in the relationship between eczema and food allergy. Although no statistically significant increase in food allergy was seen across most estimates provided by the BEEP study (whether reported at 2, 3, 4 and 5 years or cumulative incidence), there is some uncertainty which ideally needs to be resolved by combining results with other studies. Stimulated by concerns of emollients possibly increasing sensitisation to food allergens and causing food allergy, some members of this team investigated the relationship between frequency of emollient use and food allergy in the enquiring about tolerance study population and found a dose–response relationship between frequency of emollient application and subsequent food allergy. 99 Although this finding was based on observational data, the relationship between emollient use and transcutaneous sensitisation to foods clearly requires further investigation. Other work supports the concept of transcutaneous sensitisation to foods, and this process could potentially be enhanced by the use of lipid-rich emollient, by rubbing the skin and by environmental traces of food allergens on parent hands or infant skin. 100 A European Union project called TRANS-FOODS, led by BEEP co-investigator Carsten Flohr, is building on these BEEP findings to try to understand how transcutaneous sensitisation to foods might be prevented. 101

Although the possibility of harms as a result of emollients used in early life seems low, small degrees of harm affecting a large population of healthy children can add up to a considerable absolute burden and attention to such concerns become a significant issue for public health intervention studies on otherwise healthy children.

Equality, diversity and inclusion

The majority of participants were recruited via secondary care sites, with the remainder via GP surgeries. While sites were mainly in Central/Northern England and London, it is unlikely that any population were systematically excluded from taking part by virtue of where they lived in the country or how they were approached.

The majority of children had mothers of white ethnicity (see Table 4, 85%), which reflects the overall mix of ethnicity the UK. 102 The high proportion of mothers (52%) or other first-degree relatives (82%) with a history of eczema reflect the inclusion criterion of ‘first degree relative with parental-reported doctor diagnosis of eczema, allergic rhinitis or asthma’.

No information was collected directly from mothers on their educational or economic status, but deprivation indices derived from participant’s home postcodes included a reasonable range (from 3 to 9).

We were conscious of the fact that severity assessment of eczema involves scoring the intensity of erythema (redness) which is traditionally underestimated in darker skin tones. 103 During our face-to-face training that included tests images, we took measures to ensure that all research nurses were aware of the need to upgrade erythema scores by 1 point as per the EASI guidance by including several images of darker skins in the training material. 104 The quality control test105 for determining the presence of visible flexural dermatitis which the nurses had to pass in order to undertake the physical assessments also included images of darker skin.

The interpretation of genetic test results is affected by the prevalence of genetic variants in different populations. The most prevalent FLG null mutations have been established in the white European population and other ethnicities have population-specific mutations. 34,106,107 To maximise inclusivity in this study we welcomed DNA collection from all participants and all samples were genotyped.

The composition of the BEEP study team was diverse with a range of content expertise from medical (dermatology, paediatrics and primary care) and nursing backgrounds. The team ethos was to always include the important contribution of trial managers, co-ordinators and administrators in emergent publications, and allow opportunities for methodologists such as statisticians (who are rarely afforded an opportunity to be first author) to lead on some publications such as this monograph. The study also allowed the development of early career investigators (such as Maeve Kelleher) who then led on funded parallel projects such as the Cochrane Individual Patient Data meta-analysis of similar studies and also Stella Lartey, who is new to the UK, who benefited from having the opportunity to gain skills in undertaking an economic evaluation in a UK context.

Patient and public involvement

Our trial was unusual for a NIHR Health Technology Assessment (HTA) Programme trial as it was the only study that successfully applied to the specific HTA call at the time to undertake definitive trials as a result of feasibility work carried out in a NIHR Programme Grants for Applied Research (PGfAR) project. Most of the critically important PPI work for the BEEP trial was undertaken in a specific eczema prevention workstream in our PGfAR award entitled ‘Setting priorities and reducing uncertainties in the prevention and treatment of people with skin diseases’. PPI in this eczema prevention workstream defined the choice of intervention, duration of the intervention period and nature of follow-up and contact and is described briefly in the methods section of this report and in full elsewhere. 42

Additional PPI work throughout the trial was critical in informing the way in which the add-on food allergy study and genetics substudy could be offered to participants resulting in both being offered as optional studies with a short additional consent procedure that resulted in excellent uptake. In addition, PPI colleagues helped to design, advertise and promote the study and to comment on and disseminate the study results as described in our methods section. It was also very beneficial to have a PPI member in the TSC as they provided an important and varied perspective throughout the trial, and in particular when disseminating the results to parents at 24 and 60 months in order to balance the positive aspects of the key study message (one less thing to do) versus the signal of possible harm (increased minor skin infections). There were no negative experiences of working with parents, carers and patients as PPI colleagues before and during the BEEP study. Although the whole team was disappointed that emollients did not prevent eczema in the BEEP study, our PPI colleagues were remarkably accepting and objective about the finding and enthusiastic about the need to disseminate our important findings.

Throughout the trial we have received positive feedback from the families and the level of engagement and enthusiasm is evidenced by the high retention rate, particularly for the longer-term follow-up at 36, 48 and 60 months. There were no negative experiences communicated to us from parents and carers who participated in the BEEP study which we suspect is due to the thorough PPI work and preparation undertaken in the proceeding Programme Grant for Applied Research.

Findings in context

The BEEP trial results contrast with the BEEP feasibility study92 where a signal on a preventive effect on eczema was found. It should be pointed out that the BEEP feasibility study was designed to test feasibility issues and was one-tenth of the size of the main BEEP trial. Reasons for the difference are unclear but could be due to chance or the fact that the outcome in the BEEP feasibility study was measured at 6 months when irritant dermatitis is more common.

Another large independent eczema prevention trial was conducted in Scandinavia (Preventing Atopic Dermatitis and ALLergies in children – PreventADALL) around the same time as BEEP and its primary outcome results for eczema were published alongside the BEEP trial in The Lancet in 2020. PreventADALL108 was a factorial cluster trial of 2397 newborns that included a skin-care intervention (bath additives and facial cream) and a food intervention (early complementary feeding of peanut, cow’s milk, wheat and egg) as well as both or neither with two primary outcomes: eczema at 12 months and food allergy at 36 months. That study found that neither the skin intervention nor food intervention reduced eczema development, with a risk difference of 3.1% (95% CI –0.3% to 6.5%) for the skin intervention and 1.0% (95% CI −2.1% to 4.1%) for food intervention, in favour of control. No safety concerns were identified.

The most important overall summary of contextual evidence to frame the BEEP study comes from the Cochrane living review of skin-care interventions to prevent eczema that includes traditional aggregate-based data and individual participant data (IPD), funded by the NIHR through the Research for Patient Benefit programme and a personal fellowship award to MK. 109 Up to July 2020, the review identified 33 trials that included 25,827 participants. Information on one or more of the review’s specified outcomes was available in 17 studies that included 5823 participants. Eleven trials with 5217 participants, 10 of which provided IPD, were included in one or more meta-analysis. The review found that risk of eczema by 1–2 years of age was not decreased by interventions for skin barrier enhancement in infancy, with a pooled risk ratio from 7 trials and 3075 participants of 1.03, 95% CI 0.81 to 1.31 (classified as moderate-certainty evidence). Time to onset of eczema was also not earlier for those receiving the intervention, with a pooled hazard ratio from 9 trials and 3349 participants of 0.86, 95% CI 0.65 to 1.14 (classified as moderate-certainty evidence). Interestingly, the skin infections signal from BEEP was also found in other studies, with a pooled increased relative risk of skin infection over the intervention period from 6 trials and 2728 participants of 1.34, 95% CI 1.02 to 1.77 (classified as moderate-certainty evidence). Only one trial (the BEEP study) provided data on food allergy outcomes.

The review failed to find any evidence that specific subgroups based on age, intervention duration, hereditary risk, FLG mutation, or classification of intervention type for risk of developing eczema are more likely to benefit from the skin-care interventions. The study also undertook a trial sequential analysis that indicates that further studies of similar interventions are unlikely to change the conclusion that emollients do not reduce eczema risk by more than 30%, although the sequential analysis was inconclusive for a RR reduction of 20%. The review also included studies which used more sophisticated emollients containing ceramides. The review concluded that skin-care interventions in early life are probably not effective for preventing eczema, and probably increase risk of skin infection, whereas the effects of such interventions on food allergy risk remain uncertain. The review also compared findings from aggregate studies versus those obtained from IPD and found that, although IPD did not significantly change the overall primary outcome risk estimates, certainty of evidence and safety outcomes were significantly different using IPD compared to aggregate data. In addition, subgroup and adherence analyses are only possible with IPD demonstrating the added value of using an IPD approach to meta-analysis. 110

An update of the review has recently been accepted for publication in the Cochrane Library. This update was planned in order to include the food allergy outcome data from the largest similar trial, PreventADALL. At the timing of the updated review, no new relevant studies with eczema outcomes were published in time to be included, so the eczema outcome at 1–3 years did not change. For food allergy, skin-care interventions during infancy may increase the risk of IgE-mediated food allergy by 1–3 years of age (RR 2.53, 95% CI 0.99 to 6.49; low-certainty evidence; 976 participants, 1 trial) but may not change risk of allergic sensitisation to a food allergen by age 1–3 years (RR 1.05, 95% CI 0.64 to 1.71; low-certainty evidence; 1794 participants, 3 trials). Pre-planned sensitivity analysis assessing food allergy by oral food challenge or investigator assessment showed similar findings (RR 1.45, 95% CI 0.98 to 2.15; low certainty evidence; 2081 participants, 2 trials). The additional results from in this Cochrane review analysis consolidate the results for food allergy diagnosed in this way that were shown in the BEEP study.

Another systematic review on the same topic using aggregate data concluded that emollients do prevent eczema in high-risk children and that the significant protective benefit is only evident where emollients were used continuously to the point of eczema outcome assessment but not when treatment was stopped before eczema assessment. 111 However, that review has been criticised for registering the review retrospectively with limited public record of pre-planned eligibility criteria, outcomes and analysis, including subgroup analyses. 112 That review also failed to include three eligible trials that were included in the Cochrane review rendering it an unreliable source of evidence for informing clinical practice.

Following the update of the Cochrane IPD meta-analysis, the 3-year results for the Scandinavian PreventADALL study has been published. 113 These showed that neither the skin-care intervention nor early complementary feeding of peanut, cow’s milk, wheat and egg from age 3 months had any influence on AD (eczema) diagnosis at 36 months. The study found early complementary feeding reduced food allergy (risk difference −1.6%, 95% CI −2.7% to −0.5%; OR 0.4, 95% CI 0.2 to 0.8) but not in the skin intervention group (risk difference 0.4%, 95% CI −0.6% to 1.5%; OR 1.3, 95% CI 0.7 to 2.3), with no evidence of an interaction effect (p = 0.98).

Study strengths and limitations

The strengths of the BEEP trial can be considered using the population, intervention, comparator, outcome framework. Participants were representative of babies born across the UK who would normally be considered at high risk of developing eczema and associated atopic disorders. The intervention was chosen to be acceptable in a previous feasibility study and was shown in pre-study experiments not to paradoxically damage the skin barrier as some emollients have been shown to do. 114 The intervention was simple and cheap and adherence to the intervention was good, especially for study with only two face-to-face contacts with the study team (baseline and at 2 years). Participants in the control group followed standard best advice for infant skin care, and contamination rates with emollients were low (< 20% as specified in our stop/go criteria for study progression). Outcomes were robust and included family reported as well as objective outcomes on the presence of eczema and eczema severity with objective outcomes measured by trained assessors blinded to allocation status. Unblinding of intervention status prior to skin examination was minimal (12 in the intervention group and 6 in the control group). As some debate exists over the validity of diagnostic criteria for eczema in early life,115 a range of eczema outcomes were used that showed consistent lack of a preventive effect. Timing of the outcome was also conducted well away from the emollient intervention period in order to avoid any potential inflation of emollient benefit due to the mild anti-inflammatory effect of the emollient concealing mild eczema. The long duration of follow-up meant that any later benefits of emollient prevention could be picked up. Additional data from the add-on genetic study provided useful insights into whether filaggrin gene mutations are an important consideration for disease stratification in such studies. The add-on food allergy study also provided useful data on the feasibility and prevalence of SPT sensitivity to common food allergens in the UK community setting and resulted in a novel pragmatic method of confirming food allergy for those not able to travel to regional test centres for oral food challenges. 59

In terms of study design, BEEP conforms to a relatively pragmatic design when considered using the PRECIS-2 (PRagmatic Explanatory Continuum Indicator Summary) tool. 116 The large sample size had sufficient power to exclude a moderate reduction of eczema incidence. Various sensitivity analyses have confirmed the stability of the main conclusions. The effects of missing data on the study conclusions have also been thoroughly explored. The independence of the BEEP study from any commercial influence from emollient manufacturers is also a study strength. Risk of bias for the BEEP study has been rated independently in a Cochrane review109 as low risk of bias for randomisation process, deviations from intended interventions, missing outcome data, outcome measurement and selection of reported results for the eczema outcomes.

The BEEP study has also generated several useful spin-off publications that have contributed to thinking about the design and conduct of eczema prevention trials including how to define an incident case,6 an algorithm for diagnosing IgE-medicated food allergy,59 a SWAT to explore strategies for enhancing follow-up in RCTs,117 an overview of methodological considerations for eczema prevention studies,32 and the value of hyperlinear palms in evaluating FLG mutations. 118

Study limitations include the risk that BEEP used the ‘wrong’ emollients. Not all emollients are the same. Some exhibit different physiological effects on skin barrier function in adults with eczema in terms of epidermal water loss, hydration, natural moisturising factor levels and response to irritant challenges. 119 Alternatively, it may be that it is critically important to start emollients immediately after birth. Although we were pleased that families started reporting using emollient at a median of 11 days after birth (IQR 7–17 days), one single-centre industry-funded study120 has suggested preventive benefit of eczema at 12 months as a result of twice-daily specially formulated emollients applied for 8 weeks of life when started early (63% within 2 weeks). Perhaps the intervention was not intense enough and rather than an ‘advice to use’ study, an efficacy study whereby emollient application was supervised and measured accurately might have shown benefit. However, such a study would not have been practical and unlikely to be translated into everyday practice. It is also worth pointing out that based on strong user feedback from our BEEP feasibility study, parents wished to have a choice of emollients for the BEEP main study. This meant that the BEEP study used two emollients which might have had slightly different barrier enhancement properties. 44 We were however unable to explore this in a meaningful sensitivity analysis as parents initially received both types of emollients and then chose which emollient they preferred when reordering. Perhaps we were wrong to ignore various forms of transient irritant eczemas that emerge in the first year of life during the intervention period, although other studies that have measured such skin findings at 3, 6 and 12 months have not found any benefit from emollients. 108 As mentioned in the introduction, it is likely that eczema represents a range of distinct phenotypes with different disease trajectories and severity, but such variation is unlikely to affect the interpretation of this study which evaluates the prevention of new onset eczema that corresponds to a well-defined phenotype depicted by the UK diagnostic criteria for eczema. The strongest predictors of eczema onset and subsequent severity are family history of atopic disease and filaggrin gene mutations. Both were explored in subgroup analyses in this study with neither showing evidence of benefit in such subgroups. Although contamination in our control was considered low (< 20%), perhaps such a degree of contamination was sufficient to mask a small preventive effect. The results of the CACE analysis (with compliance defined as widespread emollient use at least 3 days per week) were consistent with the main analysis of no difference; however, the CIs for the CACE estimate were wider. Due to the pragmatic low-contact efficient study design, we inevitably used parental report for many of the outcomes such as skin infections and allergic diseases at 3, 4 and 5 years. Such unmasked outcome assessment is perhaps a potential source of information bias. We mitigated such bias by mainly asking for parental report of doctor-diagnosed skin infections or allergic disease. We would also argue that capturing parental report of such illnesses are important as not all families who are used to dealing with eczema will necessarily take a child with mild disease to a healthcare professional. Studies comparing parental report of the UK diagnostic criteria for eczema have also shown them to be equally valid when compared with research nurses’ assessed findings. 121 The findings from parental reports were also consistent with findings from the research nurse assessors for eczema presence and eczema severity who were masked from intervention or control status at the 2-year primary outcome assessment. Information bias as a result of enthusiasm for the intervention is also perhaps more likely to have resulted in a positive benefit for eczema prevention, whereas the study showed consistent null effects regardless of the timing and choice of outcome. The trial was not powered to detect interaction effects in subgroup analysis meaning that there is considerable uncertainty in the interaction effects (shown through wide 95% CIs) between subgroups and the effect of the intervention including for presence of FLG mutations.

Although the spread of our centres was reasonable representative of English cities and towns, we could have been more inclusive by considering translation of written materials at the study outset. Although the proportion of mothers of white ethnicity in BEEP is broadly reflective of the UK, we could have done more to reach out to under-represented groups using such frameworks as INCLUDE that appeared towards the end of this study. 122

Recommendations for clinical practice

Based on the findings of the BEEP study and the emerging evidence from other similar studies, summarised in an ongoing living systematic review that uses individual patient data meta-analysis, emollients cannot be recommended for primary prevention of eczema. Small benefits cannot be excluded, but the burden of applying whole-body emollients daily for the first year of life is considerable, and uncertainty exists about possible signals of harm in terms of skin infections and food allergy.

The use of emollients for eczema prevention should not be confused with use of emollients for eczema treatment. Emollients should continue to be used as part of standard treatment for eczema along with topical corticosteroids and calcineurin inhibitors and systemic therapies for more severe disease. In addition to treating the symptoms of dry skin associated with eczema, emollients may contribute to reducing flares (secondary prevention). 123 A recent NIHR HTA study suggests that there is little difference between the efficacy of emollient types (creams, ointments, gels or lotions) for eczema treatment in the community but patient and carer preference for each formulation varies. 124

Recommendations for future research – specific and general

Apart from the PreventADALL study, emollient prevention studies to date have focused on barrier enhancement in early life to prevent eczema in high-risk children on the basis that the preventive fraction is likely to be higher in this group when compared to others. The assumption that potential preventive benefits are likely to be higher in high-risk babies may be untrue, as it is possible that babies born to high-risk families inherit such a strong deviation in immunological responses that any potential benefit of barrier enhancement is overcome by the inherited prevailing immunological dysfunction. Studies evaluating emollients for the prevention of eczema in all (including lower risk children) may be useful to provide a complete the picture. Such a study (the CASCADE trial)125 is underway in the USA recruiting around 1250 infant/parent dyads from community settings in Oregon, Colorado, Wisconsin and North Carolina. Future studies should describe and define the phenotype of eczema that develops in the infants participating in prevention studies using well-established diagnostic criteria for defining incident cases6 and by describing the severity and trajectory of such cases once they develop. Many transient irritant forms of eczema may develop in the first year of life most of which probably do not develop into eczema,7 so care should be taken in following up such cases to see if they evolve into persistent eczema. Candidate emollients tested in future studies should ideally be tested for their skin barrier properties on infant skin. Measurement of eczema should also be done well away from the intervention period, for example, 1 year after the intervention has ceased as in the BEEP study, in order to avoid masking any potential mild eczema by the use of emollients.

With around 33 similar studies published or in progress, we suggest that enough studies on emollients for eczema prevention in high-risk families have now been set up and/or completed. Large independent high-quality studies are always welcome, but the addition of a lot of smaller studies is unlikely to help as indicated by the trial sequential analysis illustrated in the ongoing Cochrane IPD review. The priority must be to try and include all existing eczema prevention studies in that Cochrane review in some form – preferably individual patient data rather than aggregate data. We predict that there could be a degree of publication bias from some studies funded by companies with a vested interest in showing a positive outcome that claim that specially formulated emollients containing ceramides or natural moisturising factors are useful in preventing eczema. Although such emollients have not appeared to work so far, we cannot exclude the possibility that such newer specialised formulations could work, and we look forward to seeing the authors share their individual patient data of all registered and non-registered trials with the living Cochrane IPD review on this topic. Some degree of heterogeneity of effects between studies is expected since not all emollients are the same. Other studies should also link their choice of emollient to functional studies of the skin barrier. Attention to measuring and pooling potential harms of daily emollients during infancy should be encouraged in all similar future studies, with more refined collection and verification of the types and severity of skin infection. Experimental studies on the role of whole-body emollients as a vehicle for inducing skin sensitisation should also be considered.

In general terms, investing in research to prevent eczema and associated diseases is important given the burden of disease in the UK and worldwide and concerns about increasing prevalence. The variation in eczema prevalence between different environmental settings and variable genetic penetrance indicates that there are important environmental determinants, which may be modifiable. Given the disappointing results of BEEP and other trials on the strategy of skin barrier enhancement in early life using moisturisers, future eczema prevention research might concentrate on strategies to reduce potentially harmful interventions such as frequent bathing, exposure to hard water and/or use of wash products126 or future molecular mechanisms led by personalised medicine to improve skin barrier formation and function. 127 Other areas warranting further investigation are interventions which might influence early immune development, including nutritional and microbial interventions during pre or postnatal life. 128 There is already some supportive evidence for probiotics during pregnancy/lactation – however the data are heterogeneous and potentially selectively reported, so the probiotic evidence may potentially be clarified through a high-quality individual patient data meta-analysis. 128

Contributions of authors

Lucy E Bradshaw (https://orcid.org/0000-0001-8382-6040) (Medical Statistician) contributed to the conception and design of the trial and the acquisition, analysis and interpretation of the data; was responsible for statistical analysis; drafted, reviewed and edited the final report; and was a member of the Trial Management Group (TMG).

Laura A Wyatt (https://orcid.org/0000-0002-9817-5356) (Trial Manager) supported the conduct of the trial; drafted, reviewed and edited the final report; and was a member of the TMG.

Sara J Brown (https://orcid.org/0000-0002-3232-5251) (Professor of Dermatology, and co-applicant) contributed to the conception or design of the trial and the acquisition, analysis, or interpretation of the data, and was responsible for the genetic analysis. Sara also contributed clinical experience of eczema or eczema trials, or both; reviewed and edited the final report and was a member of the TMG.

Rachel H Haines (https://orcid.org/0000-0001-7924-0602) (Senior Trial Manager) contributed to the conception or design of the trial and the acquisition, analysis, or interpretation of the data and supported the design and conduct of the trial; reviewed and edited the final report and was a member of the TMG.

Alan A Montgomery (https://orcid.org/0000-0003-0450-1606) (Professor of Medical Statistics and Clinical Trials, Senior Statistician and co-applicant) contributed to the conception or design of the trial and the acquisition, analysis or interpretation of the data and was responsible for statistical analysis; reviewed and edited the final report and was a member of the TMG.

Michael R Perkin (https://orcid.org/0000-0001-9272-2585) (Consultant in Paediatric Allergy and co-applicant) contributed to the conception or design of the trial and the acquisition, analysis or interpretation of the data; supported the food allergy assessment and reviewed and edited the final report.

Tracey H Sach (https://orcid.org/0000-0002-8098-9220) (Professor of Health Economics, and co-applicant) contributed to the conception or design of the trial and the acquisition, analysis or interpretation of the data, and was responsible for the health economic design and analysis; drafted, reviewed and edited the final report; and was a member of the TMG.

Sandra Lawton (https://orcid.org/0000-0002-6163-5822) (Nurse Consultant Dermatology and co-applicant) contributed to the conception or design of the trial and the acquisition, analysis or interpretation of the data, and contributed clinical experience of eczema or eczema trials, or both; reviewed and edited the final report; and was a member of the TMG.

Carsten Flohr (https://orcid.org/0000-0003-4884-6286) (Professor of Dermatology) contributed to the conception or design of the trial and the acquisition, analysis or interpretation of the data, and contributed clinical experience of eczema or eczema trials, or both; reviewed and edited the final report.

Matthew J Ridd (https://orcid.org/0000-0002-7954-8823) (NIHR Clinical Trials Fellow and co-applicant) contributed to the conception or design of the trial and the acquisition, analysis or interpretation of the data, and contributed clinical experience of eczema or eczema trials, or both; reviewed and edited the final report.

Joanne R Chalmers (https://orcid.org/0000-0002-2281-7367) (Senior Research Fellow and co-applicant) contributed to the conception or design of the trial and the acquisition, analysis or interpretation of the data, and supported the design and conduct of the trial; reviewed and edited the final report; and was a member of the TMG.

Joanne Brooks (https://orcid.org/0000-0003-2456-0160) (Trial Coordinator) contributed to the conduct of the trial (data collection and management).

Richard Swinden (https://orcid.org/0000-0001-9877-8301) (Trial Coordinator) contributed to the conduct of the trial (data collection and management).

Eleanor J Mitchell (https://orcid.org/0000-0002-6998-4533) (Associate Professor) contributed to the conception or design of the trial and the acquisition, analysis or interpretation of the data and supported the design and conduct of the trial; reviewed and edited the final report.

Stella Tarr (https://orcid.org/0000-0001-8990-4425) (Data Manager) contributed to the conduct of the trial (data collection and management).

Nicola Jay (https://orcid.org/0000-0003-1388-192X) (Consultant Paediatrician Respiratory and Allergy and co-applicant) contributed to the conception or design of the trial and the acquisition, analysis or interpretation of the data, and supported the food allergy assessment; reviewed and edited the final report.

Kim S Thomas (https://orcid.org/0000-0001-7785-7465) (Professor of Applied Dermatology Research and co-applicant) contributed to the conception or design of the trial and the acquisition, analysis or interpretation of the data and supported the design and conduct of the trial, and contributed clinical experience of eczema or eczema trials, or both; reviewed and edited the final report.

Hilary Allen (https://orcid.org/0000-0002-7013-0308) (General Practitioner) contributed to additional analysis of the food allergy data; reviewed and edited the final report.

Michael J Cork (https://orcid.org/0000-0003-4428-2428) (Professor of Dermatology and co-applicant) contributed to the conception or design of the trial and the acquisition, analysis or interpretation of the data, and provided expertise in emollients and the skin barrier; reviewed and edited the final report.

Maeve Kelleher (https://orcid.org/0000-0002-3764-0461) (Honorary Consultant in Paediatric Allergy) supported the food allergy assessment, reviewed and edited the final report.

Eric L Simpson (https://orcid.org/0000-0003-0853-0252) (Associate Professor in Dermatology, and co-applicant) contributed to the conception or design of the trial and the acquisition, analysis or interpretation of the data, and contributed clinical experience of eczema or eczema trials, or both; reviewed and edited the final report.

Stella T Lartey (https://orcid.org/0000-0001-9519-7886) (Lecturer) contributed to the health economic analysis and reviewed and edited the final report.

Susan Davies-Jones (Research Nurse) contributed to the conception or design of the trial and the acquisition, analysis, or interpretation of the data, and contributed clinical experience of eczema or eczema trials, or both; reviewed and edited the final report.

Robert J Boyle (https://orcid.org/0000-0002-4913-7580) (Consultant in Paediatric Allergy and co-applicant) contributed to the conception or design of the trial and the acquisition, analysis, and interpretation of the data, and led the food allergy assessments; reviewed and edited the final report; and was a member of the TMG.

Hywel C Williams (https://orcid.org/0000-0002-5646-3093) (Professor of Dermato-Epidemiology and Chief Investigator). Hywel conceived the trial, contributed to the design of the trial and the acquisition, analysis and interpretation of the data; drafted, reviewed and edited the final report; and was a member of the TMG.

Acknowledgements

Additional funding for the food allergy and sensitisation tests was obtained from Goldman Sachs Gives and the Sheffield Children’s Hospital Research Fund (reference CA15008). Research nurse support was provided by the NIHR Clinical Research Networks.

The trial was developed with and supported by the UK Dermatology Clinical Trials Network (UK DCTN). The UK DCTN is grateful to the British Association of Dermatologists and the University of Nottingham for financial support of the Network.

We would like to thank the parents and infants who took time to participate in this trial, and the patients who contributed to trial design by providing helpful feedback at different stages of trial development.

We would like to thank the independent members of the Trial Steering Committee: Sarah Meredith, (Chair, Medical Research Council Clinical Trials Unit at University College London), Angela Crook (Statistician, Medical Research Council Clinical Trials Unit at University College London), Paula Beattie (Dermatologist, Royal Hospital for Children, Glasgow), Kirsty Logan (Paediatric Epidemiologist, King’s College London) and Emma Thomas (patient representative). Michael Perkin (St George’s, London) was previously an independent member of the TSC prior to becoming part of the team involved in the food allergy assessment.

We would also like to thank the following for their work on BEEP at the Nottingham Clinical Trials Unit:

• Jim Thornton for work on the grant application during his time as deputy director of the NCTU.

• Clinical Research Facilitator: Trish Hepburn.

• Senior Trial Manager: Rebecca Haydock.

• Trial Managers: Amy Moody, Angela Pushpa-Rajah, Sandip Stapleton.

• Trial Co-ordinators: Margherita Carucci, Louisa Gray, Juliet Jackson.

• Trial Administrators: Jennifer White, Andrew Jadowski, Gurmit Dhanjal, Aneesa Mehmood.

• Database Programmers: Daniel Simpkins, Keith Whitaker, Chris Rumsey.

• Data Management: Sarah Walker, Jessica Haywood, Lisa Evans.

• Statisticians: Reuben Ogollah (assistance with CACE analysis), Chris Partlett (independent validation of primary outcome, main food allergy outcome and skin infection outcome) and Grace Holt (independent validation of the UKWP AD tertiary outcome).

We would like to acknowledge and thank Dr Charlotte Davies (RAND corporation) who contributed to earlier versions of the health economic evaluation analysis undertaken using the 24-month data.

The genetic analysis work was co-ordinated by SJB at the Skin Research Group, School of Medicine, University of Dundee. During this time SJB also worked clinically at the Ninewells Hospital and Medical School, Dundee. We would like to thank Sheila C Wright (Skin Research Group, Division of Molecular and Clinical Medicine, University of Dundee, UK) for cataloguing and processing the saliva samples for DNA analysis.

Data-sharing statement

All data requests should be submitted to the corresponding author for consideration. Access to anonymised data may be granted following review.

The study protocol, SAP and HEAP are available on the trial website and the NIHR journals library. All other related documents are available on request to Prof. Hywel C Williams as chief investigator of the BEEP trial, at any point.

Ethics statement

The trial was approved by the NRES Committee West Midlands – Solihull (REC reference 14/WM/0162) on 9 June 2014 prior to the start of recruitment.

Information governance statement

The University of Nottingham is committed to handling all personal information in line with the UK Data Protection Act (2018) and the General Data Protection Regulation (EU GDPR) 2016/679. Under the Data Protection legislation, the University of Nottingham is the Data Controller, and you can find out more about how we handle personal data, including how to exercise your individual rights and the contact details for our Data Protection Officer here: https://www.nottingham.ac.uk/governance/records-and-information-management/contact.aspx.

Disclosure of interests

Full disclosure of interests: Completed ICMJE forms for all authors, including all related interests, are available in the toolkit on the report publication page of NIHR Journals Library at https://doi.org/10.3310/RHDN9613.

Primary conflicts of interest: Sara Brown holds a Wellcome Trust Senior Research Fellowship in Clinical Science (reference 106865/Z/15/Z and 220875/Z/20/Z). Alan Montgomery was a member of NIHR HTA Clinical Trials and Evaluations Funding Committee 2015–21 but had no part in the decision-making for funding this study. Tracey Sach was a member of NIHR HTA Efficient Study Designs – 2, HTA Efficient Study Designs Board, HTA End of Life Care and Add-on-Studies, HTA Primary Care Themed Call Board and the HTA Commissioning Board between 2013 and December 2019. She is a steering committee member of the UK Dermatology Clinical Trials Network and Chair of the NIHR Research for Patient Benefit Regional Advisory Panel for the East of England. Tracey had no part in the decision-making for funding this study. Carsten Flohr is Chief Investigator of the UK NIHR-funded TREAT (ISRCTN15837754) and SOFTER (ClinicalTrials.gov: NCT03270566) trials as well as the UK-Irish Atopic Eczema Systemic Therapy Register (A-STAR; ISRCTN11210918) and the Principal Investigator in the European Union (EU) Horizon 2020-funded BIOMAP Consortium (www.biomap-imi.eu/). He also leads the EU Joint Program Initiative Trans-Foods and the UK Medical Research Foundation-funded consortia. His department has received funding from Sanofi-Genzyme and Pfizer for skin microbiome work. Carsten received a grant from the EU IMI grant scheme (Horizon 2020), outside of the submitted work. Maeve Keller holds an NIHR Transitional Research Fellowship (TRF-2017–10–003). Matthew Ridd holds a Post-Doctoral Research Fellowship from NIHR (PDF-2014–07–013). Matthew Ridd was a member of HTA General Committee and ESP Evidence Synthesis Programme Advisory Group. Michael Cork received institutional research grants and personal consulting fees from Hyphens Pharma, L’Oréal and Perrigo (ACO Nordic). Michael is on the advisory board for L’Oréal and was a member of the Board of the European Academy of Dermatology and Venereology (EADV) and is a voluntary medical advisor to the National Eczema Society, UK. Eric Simpson reports personal fees from AbbVie, Amgen, Arena Pharmaceuticals, Aslan Pharma, Boston Consulting Group, Collective Acumen LLC (CA), Dermira, Eli Lilly, Evidera, ExcerptaMedica, Forte Bio RX, Galderma, GlaxoSmithKline, Incyte, Janssen, Kyowa Kirin Pharmaceutical Development, Leo Pharm, Medscape LLC, Merck, Pfizer, Physicians World LLC, Regeneron, Roivant, Sanofi-Genzyme, Trevi therapeutics, Valeant, WebMD. Eric Simpson also reports grants (or Principal investigator role) from AbbVie, Amgen, Arcutis, Aslan, CorEvitas, Dermavant, Dermira, Eli Lilly, Incyte, Kymab, Kyowa Hakko Kirin, Leo Pharmaceuticals, Pfizer, Regeneron, Sanofi, and TARGET-DERM. These potential conflicts of interest have been reviewed and managed by OHSU. Robert Boyle received personal fees from Cochrane, Wiley, British Society of Allergy and Clinical Immunology for editorial work and fees for expert witness work, outside of the submitted work. Robert’s employing institution Imperial College London has a formal research and innovation partnership with Nestlé, who manufactures and markets nutritional products for managing food allergy and sponsor infant nutrition research related to eczema and food allergy. Hywel Williams was director of the NIHR Health Technology Assessment Programme from 2015 to 2020. Hywel Williams was a member of the HTA Antimicrobial Resistance Themed Call Board, HTA Commissioning Sub-Board, HTA Efficient Study Designs – 2, HTA Efficient Study Designs Board, HTA Funding Teleconference Member, HTA Surgery Themed Call Board, NIHR CTU Standing Advisory Committee, NIHR Journals Library Board, PGfAR EOIs – HTA projects Remit meeting, Pre-Exposure Prophylaxis Impact Review Panel, HTA Remit and Competitiveness Group, HTA General Committee, HTA Post-Funding Committee teleconference, HTA Funding Committee Policy Group and HTA Commissioning Committee. Hywel had no part in the decision-making for funding this study. All other authors declare no competing interests.

Patient data statement

This work uses data provided by patients and collected by the NHS as part of their care and support. Using patient data is vital to improve health and care for everyone. There is huge potential to make better use of information from people’s patient records, to understand more about disease, develop new treatments, monitor safety and plan NHS services. Patient data should be kept safe and secure, to protect everyone’s privacy, and it is important that there are safeguards to make sure that they are stored and used responsibly. Everyone should be able to find out about how patient data are used. #datasaveslives You can find out more about the background to this citation here: https://understandingpatientdata.org.uk/data-citation

Publications

Bradshaw LE, Haines RH, Thomas KS, Chalmers JR, Irvine AD, Williams HC, Brown SJ. Clinical examination for hyperlinear palms to determine filaggrin genotype: a diagnostic test accuracy study. Clin Exp Allergy 2021;51:1421–28. https://doi.org/10.1111/cea.14025. Epub 18 October 2021. PMID: 34608691.

Bradshaw LE, Montgomery AA, Williams HC, Chalmers JR, Haines RH. Two-by-two factorial randomised study within a trial (SWAT) to evaluate strategies for follow-up in a randomised prevention trial. Trials 2020;21:529. https://doi.org/10.1186/s13063-020-04373-4. PMID: 32546180; PMCID: PMC7296963.

Bradshaw LE, Wyatt LA, Brown SJ, Haines RH, Montgomery AA, Perkin MR, et al. Emollients for prevention of atopic dermatitis: 5-year findings from the BEEP randomized trial. Allergy 2023;78:995–1006. https://doi.org/10.1111/all.15555. Epub 3 November 2022. PMID: 36263451.

Chalmers JR, Haines RH, Bradshaw LE, Montgomery AA, Thomas, KS, Brown SJ, et al. Daily emollient during infancy for prevention of eczema: the BEEP randomised controlled trial. Lancet 2020;395:962–72. https://doi.org/10.1016/S0140-6736(19)32984-8

Chalmers JR, Haines RH, Mitchell EJ, Thomas KS, Brown SJ, Ridd M, et al. Effectiveness and cost-effectiveness of daily all-over-body application of emollient during the first year of life for preventing atopic eczema in high-risk children (The BEEP trial): protocol for a randomised controlled trial. BMC Trials 2017;18:343. https://doi.org/10.1186/s13063-017-2031-3

Kelleher MM, Cro S, Van Vogt E, Cornelius V, Lodrup Carlsen KC, Ove Skjerven H, et al. Skincare interventions in infants for preventing eczema and food allergy: a cochrane systematic review and individual participant data meta-analysis. Clin Exp Allergy 2021;51:402–18. https://doi.org/10.1111/cea.13847. Epub 25 February 2021. PMID: 33550675.

Overgaard LEK, Main KM, Frederiksen H, Stender S, Szecsi PB, Williams HC, Thyssen JP. Children with atopic dermatitis and frequent emollient use have increased urinary levels of low-molecular-weight phthalate metabolites and parabens. Allergy 2017;72:1768–77. https://doi.org/10.1111/all.13157. Epub 4 April 2017. PMID: 28281298.

Perkin MR, Logan K, Marrs T, Radulovic S, Craven J, Boyle RJ, et al.; EAT Study Team. Association of frequent moisturizer use in early infancy with the development of food allergy. J Allergy Clin Immunol 2021;147:967–76.e1. https://doi.org/10.1016/j.jaci.2020.10.044. PMID: 33678253.

Van Vogt E, Cro S, Cornelius VR, Williams HC, Askie LM, Phillips R, et al. Individual participant data meta-analysis versus aggregate data meta-analysis: a case study in eczema and food allergy prevention. Clin Exp Allergy 2021. https://doi.org/10.1111/cea.14085. Epub ahead of print. PMID: 34939249.

Disclaimers

This article presents independent research funded by the National Institute for Health and Care Research (NIHR). The views and opinions expressed by authors in this publication are those of the authors and do not necessarily reflect those of the NHS, the NIHR, the HTA programme or the Department of Health and Social Care. If there are verbatim quotations included in this publication the views and opinions expressed by the interviewees are those of the interviewees and do not necessarily reflect those of the authors, those of the NHS, the NIHR, the HTA programme or the Department of Health and Social Care.