Title: Assessing the efficacy and safety of methotrexate vs ciclosporin in the treatment of severe atopic eczema in children: the TREatment of severe Atopic eczema in children Taskforce (TREAT) randomised controlled trial
Funder: Department of Health and Social Care

Abstract: HYPOTHESIS AND AIMS: The main aim is to evaluate the treatment efficacy & safety of oral methotrexate (MTX) vs ciclosporin (CyA) in the treatment of severe atopic eczema (AE) in children. We hypothesise that: -CyA vs MTX is more efficacious in reducing disease severity at 12 weeks, -both drugs have similar efficacy at 36 weeks, & -children who were treated with MTX see a lower risk of disease flares up to 6 months after stopping treatment compared to CyA. We will also examine the effect of MTX & CyA on novel systemic & cutaneous markers of inflammation during & up to 6 months after treatment. We hypothesise that MTX (vs CyA) induces a net anti-inflammatory effect that re-programmes the disease process, leading to a reduced risk of flares after treatment cessation. DESIGN: multi-centre RCT POPULATION: Children age 2-16 years with severe AE (o-SCORAD=40), unresponsive to potent topical treatment. Children should not have received UV light therapy within the past 6 months & never any systemic immuno-suppressive therapy, except for oral corticosteroids for acute flares. INTERVENTION: CyA: 4mg/kg/day; MTX: started at 0.1mg/kg/week & accelerated to 0.4mg/kg/week over a month. Both drugs will be given for 9 months. OUTCOMES: PRIMARY OUTCOME: Change in AE severity between baseline & 12 weeks of treatment, using the objective SCORing Atopic Dermatitis (o-SCORAD) severity index. SECONDARY OUTCOMES: - risk of flares during the 6 months after treatment cessation in the MTX vs CyA groups - change in AE severity using the EASI, IGA & patient-oriented (po)-SCORAD scores between baseline & 12, 36, 60w & using the o-SCORAD at 36, & 60w - quality of life: change in CDLQI/IDQOL & DFI scores between 0 & 12, 36, & 60w - immuno-metabolic effects of MTX & CyA during & after treatment - MTX metabolite & CyA trough levels & their association with reduction in AE severity/side effects - effect of FLG genotype & T cell cytokine signature on reduction in AE severity ASSESSMENTS: Severity measures: 0, 4, 8, 12, 24, 36, 48 & 60w Disease flares, side effects & adverse events: each follow up point Quality of life scores: 0, 12, 36 & 60w Bloods safety profiles: 0, 1, 4, 8, 12, 24, 36 & 60w Mechanistic work: 0, 12, 36, & 60w SAMPLE SIZE: The study aims to detect a difference of 8 points (SD 10) in o-SCORAD. A sample size of 40 per group is required (90% power at the 0.05 significance level). STATISTICAL ANALYSIS: Continuous data will be reported as difference in means & will be analysed using ANCOVA were appropriate & binary data will be reported in terms of relative risk with 95% confidence intervals. ECONOMIC BENEFIT: CyA is currently the most commonly prescribed first line systemic medication in children with severe AE. While it is efficacious in the short-term, renal side effects limit its long-term use. It is also more costly than MTX. If our hypotheses are true, then MTX could replace CyA as first line systemic treatment. The proposed mechanistic work promises to explain the putative disease-modifying effect of MTX & the discovery of new therapeutic targets. DURATION OF THE STUDY (RECRUITMENT RATE, JUSTIFICATION FOR ESTIMATE, MAIN STAGES OF THE PROJECT WITH EXPECTED DURATIONS) Month 1-9: trial set up (ethics, site initiation). Month 10-27: Recruitment (rate 1 participant/quarter/site). Month 28-42: follow up visits, data entry & data querying. Month 43-48: final data entry, analysis & report writing.

Lay abstract: We are proposing a study of the effectiveness and safety of two immunosuppressive medicines, methotrexate (MTX) and ciclosporin (CyA), in the treatment of severe, difficult to manage eczema in children. Eczema affects 1 in 4 children in the UK. It causes inflamed, itchy skin and typically affects the folds of the body such as behind the knees, inside the elbows as well as the neck. Flare ups are common and the impact on health service costs and patients’ and families’ quality of life is similar to diabetes or asthma. Eczema treatment aims to reduce the skin inflammation, relieve itching and prevent flare-ups. Usually, this can be achieved with regular application of emollients and steroid creams and the majority of children grow out of their eczema over time. However, in a small group of patients the disease is so severe that immuno-suppressive medication is required. So far, there has been very limited research into this area in children, and clinical management is therefore primarily guided by studies performed in adults. A survey we conducted among dermatologists in 8 European countries showed that CyA is the by far commonest immuno-suppressive medication used in children. However, it can have a negative effect on kidney function, the eczema often flares after stopping the medication, and it is expensive. There is therefore a need to find alternative treatments, as highlighted by a recent priority setting exercise in the UK, which included medical experts, parents and patients with eczema. MTX, in addition to the more widely used CyA, was specifically mentioned, partly because there are now two small studies suggesting that it could be an effective alternative to CyA. Studies in children with rheumatoid arthritis suggest that MTX’s tolerability and long-term safety profile is good. In addition, it is cheaper than CyA. We propose to investigate the benefit (efficacy) of CyA vs. MTX in the treatment of severe eczema that has not responded to regular application of emollients and potent topical corticosteroids. In addition to the effect on disease severity, we will compare the impact on patients’ quality of life after 12 and 36 weeks of treatment and for six months after stopping MTX and CyA. We will also study how well the two medications control flares and their safety and tolerability (adverse reactions). Although MTX has been extensively used in a number of diseases, such as rheumatoid arthritis, we do not know how it works, and this will also be examined in our trial. For this, blood tests will be required but not more frequently than during routine NHS clinical care. We will also use a special sticky tape to collect samples from the skin of participating children. This is not traumatic and will allow us to study the immune response in the skin. Patients will be recruited through the main Anglo-Irish paediatric dermatology departments. The study team has vast experience in conducting clinical trials and consists of children’s dermatologists, research methodologists and experts in dermatopharmacology (drug reactions) and immunobiology (inflammation and immune cell interactions). The study will be submitted to UK and Irish ethics committees and regulatory authorities, where all aspects of the study will be assessed. Independent monitoring throughout the study will ensure that it is conducted to the highest international standards.

Research activity codes: 5.1 PHARMACEUTICALS;6.1 PHARMACEUTICALS
Health categories: SKIN