Title: Best systemic treatments for adults with atopic eczema over the long term (BEACON): A randomised, assessor-blind trial comparing ciclosporin, methotrexate and dupilumab
Funder: Department of Health and Social Care

Abstract: Eczema is a very common skin disease that affects one in 20 UK adults. People with eczema itch constantly. This leads to sleep loss. The damaged inflamed skin often gets infected and leads to disfigurement, low mood and a big negative impact on quality of life. Eczema is caused by a combination of genes, a weakened skin barrier, changes in the immune system and outside triggers (such as allergens)._x000D_ _x000D_ Mild eczema can usually be controlled with creams/ ointments. More severe disease needs ‘systemic’ treatments (taken by mouth or injection) such as methotrexate and ciclosporin that dampen down the immune system. Recently, treatments have been developed to block signals from one type of immune cell (T helper 2 cell or Th2) that is particularly important in eczema and related diseases such as asthma. Dupilumab is the first of these to be available on the NHS but so far studies have only compared dupilumab with placebo (dummy drug), not the standard treatments, so we do not know which is best._x000D_ _x000D_ The aim of this trial is therefore to compare the effectiveness of dupilumab (the new targeted treatment) and methotrexate (the most commonly used standard systemic treatment) to ciclosporin (the only licensed standard systemic treatment). We will also compare their side effects, how well they are tolerated by patients and costs._x000D_ _x000D_ In this trial, adults with moderate to severe eczema who need systemic treatment will get either ciclosporin as an oral capsule, methotrexate self-injection or dupilumab self-injection for up to one year. Which treatment they receive will be decided at random (computer generated). Patients will know which treatment they have received but the trained person assessing the eczema will not know to make sure we come up with a truthful answer on which is best. Between 6 and 14 check-ups at hospital and over the telephone/ internet would be done throughout the year as per normal NHS care. People who take part will also fill in online questionnaires in between visits about any side-effects they have noticed and whether they have used any other NHS services. There will be an option to increase the treatment dose after 3 months and at 6 months the treatment can be changed if it is not working well enough. We will judge the success of the different treatments by looking at participants’ skin using a reliable eczema score and by asking participants about things like itching and quality of life. We will collect information about side effects and also see whether the treatments offer value for money for our NHS._x000D_ _x000D_ This trial will tell us which medicine works best for adults with moderate to severe eczema and which one offers best value for money for the NHS. The study will also find out the best overall treatment path over 1 year. We will work with the Medical Research Council Clinical Trials Unit to set up this trial in a way that, with future funding, the 20 or so new eczema treatments in development can be added one by one so we can efficiently compare them against the best treatment (“standard of care”) on a level playing field, a so-called “multi-arm, multi-stage platform trial”. _x000D_ _x000D_ We have worked with eczema patients and the National Eczema Society (NES) in designing this study and we will continue to work with them as partners throughout the trial. We will make sure that we tell everyone about our results by working with our patient community, NES and the various professional networks that we belong to.

Lay abstract: Research question: What is the most effective, tolerable and cost-effective systemic therapy to treat moderate-severe adult atopic eczema?_x000D_ _x000D_ Background: Atopic eczema (eczema) is the most common inflammatory adult skin disease. It presents with itchy, sore, inflamed skin that leads to scratching, infection and sleep loss along with significant psychological and social impairment. Moderate to severe disease (around 10% of the eczema population) usually requires systemic therapy with commonly used treatments including ciclosporin (the only licensed standard therapy), methotrexate and dupilumab (a novel, targeted therapy). There is clinical equipoise as to which intervention is best, and no active comparator data for dupilumab. _x000D_ _x000D_ Aims and objectives: To determine the effectiveness, tolerability and cost-effectiveness of dupilumab and methotrexate compared with ciclosporin in adults with moderate to severe eczema; to identify the optimal treatment pathway over one year; to use a platform design to enable future, additional comparator arms. _x000D_ _x000D_ Methods: This is an assessor-blind, randomised controlled trial. Adults with at least moderate disease will receive dupilumab (subcutaneous), methotrexate (subcutaneous) or ciclosporin (oral) randomised 1:1:1. The primary outcome (blinded) will be objective disease severity at 6 months using the core outcome measure of Eczema Area and Severity Index (EASI); secondary endpoints relate to symptoms (itch, disease control), quality of life, depression, anxiety, safety and cost effectiveness. Participants will be assessed at months 0, 1, 3 and 6 with an optional dose increase at month 3. At 6 months, treatment will be continued for a further 6 months if defined effectiveness criteria are met, or switched to an alternative therapy in line with NICE guidance (dupilumab to methotrexate, ciclosporin/methotrexate to dupilumab). The sample size of 402 gives 90% power to detect a mean absolute difference of 6.6 (minimal clinically important difference (MCID)) in EASI (superiority for methotrexate or dupilumab against ciclosporin; if treatment benefit is demonstrated for both, methotrexate will be compared against dupilumab). Q learning methods will be used in a secondary analysis to identify the pathway that optimises outcomes at 12 months. _x000D_ _x000D_ Timelines: Forty eight months to deliver this project is realistic given the experience and track record of the research team, established network of recruiting centres, and requisite infrastructure and operational support through the Clinical Trials Unit at Kings, NIHR Clinical Research Network and UK Dermatology Clinical Trials Network. _x000D_ _x000D_ Impact: This trial will provide the first comprehensive head to head evidence on the comparative effectiveness, tolerability and cost effectiveness of the three key systemic agents used to treat moderate-severe adult eczema, and the optimal 12 month treatment pathway. These data will translate into improved health outcomes, minimise treatment switching, and enable healthcare commissioning based on clinical evidence and value for money. Partnership with the National Eczema Society and input from patients means that our findings are relevant to patients’ needs. This trial will be set up to facilitate future transition into a multi-arm multi-stage platform trial that can evaluate new biologic and oral therapies for eczema.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: SKIN