A randomised placebo-controlled study examining the role of anti-IgE in severe recalcitrant paediatric atopic eczema

Eczema is a skin condition affecting up to 22% of children. Some children with eczema have it so severely that they fail to respond to routinely available treatment. Eczema has an impact on both the child’s and their family’s quality of life, with constant itching and disturbed sleep. IgE is produced by the immune system, and may be important in children with eczema. The aim of this study is to use the drug, anti-IgE (omalizumab), to see if this reduces the levels of IgE in children with eczema, and improves their symptoms. We plan to treat children whose eczema is not controlled by the usual moisturising, steroid and the newer calcineurin inhibitor creams. These children have such severe disease that they are not even helped by oral drugs, which can also cause serious side effects. These are the children we would like to treat with anti-IgE. Our aims would be to relieve the symptoms of eczema, and reduce the amount of oral treatment that they need. This research will be carried out in the Children's Allergy Service and St. John's Institute of Dermatology at Guy's and St. Thomas' Hospitals NHS Foundation Trust(GSTT), the largest such services in the UK. Two of the doctors involved in this research run a joint Allergy & Dermatology clinic, where children with some of the most severe forms of eczema are seen. The participants will be recruited from this setting, and from local hospitals. The study will be performed in the 6 bedded children’s Research ward in the Evelina Children's Hospital. Half the children recruited into the study will be treated with anti-IgE for 6 months, whilst the other half will have a dummy treatment(placebo). The children will be monitored throughout with assessments of their eczema score (SCORAD). We will also examine other outcomes, such as any changes in their quality of life as a result of the treatment. Ethical approval for this study has been granted by the Research Ethics Committee(London- Westminster) and Regulatory approval has been granted by the Medicines and Healthcare products Regulatory Agency (MHRA). This study has received partial funding from the Guy’s and St. Thomas’ Charity. After the initial NIHR EME application was submitted, the drug manufacturer, Novartis, has agreed to fund the drug and placebo. Additional safety monitoring has been put in place and NIHR EME funding will allow these additional costs to be met. It will also meet the costs for medical supervision and to meet the additional salary costs of a full time research nurse. Following recommendations by the NIHR EME board, we have included statistical and CTU support for this study. The use of facilities and input of other medical staff will be borne by the institution.

Research design: A double blind randomised placebo-controlled study comparing anti-IgE to placebo in children with severe eczema. Study population: Inclusion criteria: a)6-19 years old b)Severe eczema: objective SCORAD(SCORing Atopic Dermatitis, a validated eczema score>40 c)Intolerance or failure of systemic therapy d)total IgE>300kU/l e) clinical history that allergic exposures cause worsening eczema f)IgE mediated allergic disease. The exclusion criteria are: a)inability to comply with the regime b)significant underlying condition, uncontrolled infection c)hypersensitivity to anti-IgE injections e)recent CTIMP Planned interventions: Therapy in the treatment arm will comprise anti-IgE (Xolair/omalizumab) injections. The placebo arm will receive matching placebo injections. Proposed outcome measures/assessment and follow up: Primary: 1. Eczema severity at 16 weeks determined by SCORAD Secondary: 1. Systemic prednisolone dosage by drug history 2. Quality of life: by questionnaire a)Patient-oriented Eczema Measure(POEM) b)Children’s Dermatology Quality of Life Index(CDLQI) 3. Eczema severity during & after therapy: by SCORAD, transepidermal water loss, photos 4. Coexisting allergic disease: spirometry, exhaled nitric oxide measurements, questionnaire(PADQLQ) 5. Side effects and safety: by blood tests for cortisol, glucose and HbA1c levels, urinary glucose monitoring, pubertal staging, growth monitoring, bone density monitoring, ophthalmology review and frequency of AEs reported. 6.Eczema exacerbations and infections. 7. Effect on specific IgE and skin tests. Secondary outcome measures will be assessed at baseline, 2-4 weekly during treatment, at the end of treatment, and at the 26, 36 and 48 week post treatment reviews. Proposed sample size: 62 patients, 31 each in the treatment and placebo arms would enable us to detect a clinically meaningful difference of 33% relative reduction in the SCORAD(by 40% from 45 to 27 points in the treatment group and by 10% from 45 to 40.5 points in the placebo group) between the treatment arms, assuming a standard deviation of 15, a significance level of 5% and 90% power, and 15% drop out rate. Statistical analysis: We will use analysis of covariance to to compare the change in SCORAD in the two groups(primary outcome). The analysis of covariance or conditional logistic regression will be used to assess the effect on systemic steroid dose, safety and side effects. Analyses will be conducted according to the intention to treat. Project timetables: In place : Research Ethics Committee(REC) and MHRA approvals, functioning clinical trial facilities. 0-6 months: Finalising details with Novartis, staff recruitment, protocol publication and amendments for REC and MHRA. 6-24 months: patient recruitment and run-in. 6-30 months: patients undergoing treatment. 12-30 months: end of treatment and assessments. 12.5-36 months: post treatment reviews. 36-39 months: data analysis and draft paper.