Title: A randomised controlled trial to determine whether skin barrier enhancement with emollients can prevent eczema in high risk children
Funder: Department of Health and Social Care

Abstract: WHY WE WANT TO DO THIS TRIAL: Childhood eczema affects one in five UK schoolchildren. Constant itching causes misery and sleep loss to children and families. Children with eczema also develop more food allergies, asthma and allergic rhinitis. Genetics and the environment are important in causing eczema and associated allergies. An imbalance in the immune system and a defective skin barrier at birth may both be important in increasing the risk of eczema. Mutations in the genes that code for filaggrin proteins (FLG) that are essential to maintaining a healthy skin barrier have consistently been shown to result in dry skin in early life plus an increased risk of eczema, severity of eczema and associated asthma. Regular application of emollients (skin moisturisers) enhance the skin barrier, but it is not known if enhancing the skin barrier from birth can reduce the onset and severity of eczema or associated allergic diseases. WHAT WE HAVE DONE TO PREPARE FOR THIS TRIAL: We conducted an overview of systematic reviews of randomised controlled trials (RCTs) on the primary prevention of eczema and showed that none of the dietary or allergen reduction interventions clearly prevented eczema. In our pilot RCT (part of our NIHR Programme Grant) we randomised 124 babies to daily emollients plus skin care advice for 6 months or skin care advice alone and showed that families were willing to take part in such a study and that contamination of the control group was low. Encouragingly, it also showed that daily emollients halved the risk of eczema developing. We have also done biomechanical studies on the skin of people with a history of eczema and shown that the two of the most popular emollients in the pilot study improve skin barrier function, and so we will use these in this main trial. WHAT WE PLAN TO DO IN THIS TRIAL: We would like to test the hypothesis that daily emollient application for 12 months after birth can reduce the onset of eczema at age 2 years. Our secondary aims are to see whether this simple, low-cost intervention can reduce the severity distribution of eczema, delay the onset of eczema that does develop, and the development of associated allergic diseases (asthma, allergic rhinitis and food allergies), whether it is cost effective and whether any effects last into later childhood. HOW WE PLAN TO DO IT: Design: A pragmatic, randomised, controlled, parallel group, multicentre, assessor-blind primary prevention trial. Health technologies being assessed: All parents will be given best practice infant skin care advice for their child. Those randomised to the intervention group will, in addition, be advised to apply emollient daily to the child’s entire body surface area for the first year of life (either Doublebase Gel® and Diprobase Cream® and may change between the two emollients throughout the trial if they wish). Measurement of outcomes: The primary outcome is a diagnosis of eczema between 12 and 24 months of age (defined as meeting the UK Working Party Diagnostic criteria). To reflect the chronicity of eczema, these criteria refer to signs and symptoms present over the past year. Applying the criteria at 24 months of age will therefore detect eczema present only between the ages of 12 and 24 months, thus excluding transient eczematous rashes which are common in the first year of life and often reported by parents as “eczema” but less likely to be true atopic eczema. Secondary outcomes are other measures of the development of eczema (parental report of a clinical diagnosis, parental completion of UK Working Party Diagnostic Criteria, and visible eczema at 2 years of age), severity of eczema, presence of other allergic diseases, quality of life, health care resource use and cost effectiveness, and safety endpoints (slippages and skin infections). We will continue to follow the children up to age of 5. Setting: Participating families will be recruited in approximately 10 centres around the UK from primary and secondary care as well as through general publicity and advertising. Target population: Babies at high risk of developing eczema and associated allergic disease, defined as having a parent or sibling who has (or had) doctor diagnosed asthma, eczema or allergic rhinitis. Sample size: Assuming that 30% of children in the control group will have eczema between one and two years of age and that a relative reduction of 30% is deemed to be of clinical importance (i.e. 21% of children in the intervention group have eczema between one and two years of age), a total of 1282 children will allow this difference to be detected at the 5% significance level (two-sided) with 90% power. This assumes equal numbers of children randomised to each group and 20% attrition. WHY IT IS IMPORTANT TO DO THIS STUDY: It is timely to conduct this trial as knowledge of skin barrier function and its relationship to eczema has expanded rapidly in the last 5 years and our pilot RCT results are promising.

Lay abstract: WHAT IS ECZEMA AND WHY IS IT IMPORTANT? Eczema is an itchy skin condition characterised by red and dry skin. It can affect any part of the body including the face, but tends to settle in skin creases, such as behind the knees, or folds of the arm and neck. It is common, affecting about 1 in 5 children and 1 in 20 adults. Asthma, hay fever and food allergy are also common in people with eczema. Although eczema gets better with age for many children with eczema, around 40% continue to suffer from eczema for the rest of their life. Severity varies widely but in some cases it can be a very disabling, resulting in time off school and sleep problems, which can affect the whole family. The cause of eczema is probably partly genetic and partly environmental. The genetic causes are probably because of mutations in a gene which codes for a crucial skin barrier protein called filaggrin, plus other genes that govern immune responses. Environmental factors probably include things like house dust mites, rough clothing, cold, dry weather and skin infections. PREVENTION IS BETTER THAN CURE… Although treatment with skin moisturisers and active drug creams such as topical steroids work fairly well, they only control symptoms. There is no drug cure for eczema. Prevention would be better, but so far none of the attempts at prevention - avoiding certain foods or introducing friendly gut bacteria - seem to work. One simple idea is to use simple skin moisturisers (emollients) from birth. The emollient is just massaged into the baby’s skin each day. There is no need for the baby to swallow any medication. Keeping the skin moisturised and avoiding dry skin might stop the early stages of the disease. If this works it would be a very cheap way to prevent a serious disease. WHAT WE PLAN TO DO: The best way to test whether this works is to do a randomised controlled clinical trial. Put simply, we divide a group of parents of children at high risk of developing eczema, into two groups at random (by chance). One group will get a skin care advice package which includes a moisturiser to use daily on their baby’s skin for twelve months from birth, and the other (the control group) will get a skin care advice package without the moisturiser. Someone who does not know what treatment each baby got will examine the child when they are two years old for signs of eczema and parents will complete questionnaires every few months during the trial. We have done a small “rehearsal” trial like this already, and shown that most parents are happy to join in, and to give the treatment or not as intended. The results were promising but so far have not proven beyond doubt that the treatment works. This is why we need this much larger national study that will involve more than a thousand babies born to families in whom at least one first degree relative has eczema, asthma or hayfever. We chose “high risk” families like this because eczema is more common in their babies, and they are more likely to be motivated to take part in such a long term study. This large study will not only be large enough to give a definitive answer, but we will also follow babies up to test the long term effects and also to see whether use of moisturisers can prevent asthma and hayfever which commonly follow on from eczema. We will also test babies for mutations in the filaggrin gene (a gene known to be involved in eczema) and see whether they are more or less likely to benefit from using moisturisers from birth. It is also important to point out that moisturisers are not always beneficial, as some like aqueous cream have been shown to actually thin the skin and make the skin barrier worse. Asking parents to apply emollients for 12 months to a health baby’s skin is quite an undertaking so it is essential that we find out if it results in lasting benefits. Doing a big study like this in a way that will come up with a fair and truthful answer is difficult and expensive, so we have assembled a strong team with expertise in researching and delivering trials in eczema, pregnancy and childbirth, general practice, emollients, genetics and in running trials. Parents of children with eczema have also been part of our team right from the start of the study and will continue to help us to get the right study design and publicity when recruiting and publishing results.

Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: SKIN