Title: Comparison of ALitretinoin with PUVA as the first line treatment in patients with severe chronic HAnd eczema (ALPHA trial)
Funder: Department of Health and Social Care

Abstract: Hand eczema (HE) is one of the most common skin disorders and an important cause for morbidity and occupational disability. HE is a heterogeneous disease which presents with various subtypes. The impact on daily life of sufferers is considerable. The 1-year prevalence of HE is estimated to be up to 10% in the general population. The proportion of patients who develop severe chronic HE (CHE) is estimated to be 5-7% of all patients with HE. HE therapy is delivered in escalating steps. When patient education, allergen/irritant avoidance and topical treatment are not sufficient to control the disease, UV therapy or systemic immune-modifying drugs are used. Alitretinoin (AL) is licensed for severe, CHE unresponsive to treatment with potent topical corticosteroids. However, currently available clinical evidence for the treatment of CHE is not compelling enough to guide clinical practice. The lack of clear evidence based data has been outlined by different national and international expert groups. Given the high socioeconomic impact of the disease there is a pressing need for comparative studies on available first line treatments, and on long-term outcome of currently used therapies. The NIHR has recognised this need and launched this commissioned call aiming to compare AL to other treatment options. Our choice of comparator for AL was based on published clinical trials, on feedback from UK dermatologists, patients and the UK Dermatology Clinical Trials Network (UKDCTN). As research and audit data on treatment choices for CHE are unavailable, we performed a survey among 194 UK dermatologists; the most frequent first choice approaches for CHE were PUVA, oral steroids and AL. When asked which strategy was thought to be most efficient for long-term outcome 20% of clinicians indicated that they did not know whilst 43% of clinicians opted for AL and 30% PUVA. Therefore, we propose a multicentre, open, prospective, two-arm parallel group, adaptive, randomised controlled trial comparing the response to the currently most common first line therapies in UK clinical practice, PUVA and AL. In line with daily clinical practice (survey results) topical steroids and moisturisers will be applied along with the intervention. Frequent assessments will be performed for 52 weeks post randomisation. The primary outcome measure will be at 12 weeks to directly compare short term response to first line treatments (and allow comparison to existing trials). Key secondary outcomes include long term outcome with focus on remission period, patient’s benefit, quality of life (QoL) and cost effectiveness outcomes including resource costs associated with patient treatment, monitoring, and productivity costs. The physician’s global assessment (PGA) will direct treatment pathways after randomisation. Patients with insufficient response to PUVA or AL will be treated according to usual clinical practice which may include switching to the alternative intervention, or immunosuppressants such as methotrexate or cyclosporine A. This will provide valuable pilot data on second line therapeutic approaches and will be useful in informing the choice of therapies in future trials. An emphasis of this study will be on eczema subgroups, patient education and patient-relevant benefits. A sub-study on molecular parameters linked to distinct eczema subgroups will give additional information on subgroup specific treatment responses.

Lay abstract: Hand eczema (HE) is one of the most common skin disorders and in severe cases the impact on daily life is considerable. Severe chronic HE (CHE) cannot be controlled satisfactorily with creams and ointments. The treatment of HE can be difficult as different factors (e.g. allergens, irritants, skin barrier defects) are involved and these can differ between patients. There is a lack of reliable data which could direct clinical practice regarding the most effective therapy if creams/ointments alone are not sufficient to control the disease. In particular, there is no reliable information on the effect of therapies within patient subgroups (e.g. depending on contributory factors). Given the high impact of the disease on working and social life there is a pressing need for studies which can inform on the effectiveness of currently used treatments for both short and long term outcomes. In appreciation of this need, the NIHR has launched a commissioned call to find out “which is the most effective treatment for severe CHE”. One of the treatments to be investigated in the study has to be Alitretinoin (AL), the only drug currently licensed specifically for the treatment of severe CHE. We plan to compare the effect of AL to that of an ultraviolet light (UV) treatment approach called PUVA (psoralen UV-A). AL and PUVA are the most frequently used first line therapies for CHE in the UK. At the start of this study all patients will have the opportunity to learn more about irritant avoidance and application of topical treatment. Patients will be randomised to receive either PUVA or AL over a 12 week period (patients who show a positive but only partial response can receive treatment for up to a total of 24 weeks). Moisturisers and defined steroid creams can be applied during the treatment period and after finishing the treatment (maintenance phase). Patients who relapse or who have not responded sufficiently to treatment will receive standard treatment as per clinical practice at each study centre. As different dermatology centres have a focus on different treatment approaches for severe CHE (e.g. methotrexate, cyclosporine A) pilot data on the effect of these treatments will be collected as well. The main aim of the study is to determine which treatment is most effective after 12 weeks of treatment. However, patients and dermatology health care professionals involved in the study design have highlighted the importance of understanding the long term effect of HE treatments. We will therefore ask patients to attend an assessment of their HE every 4 weeks up to week 36 and every 8 weeks thereafter over a period of 52 weeks. This will allow us to monitor the response to the initial treatment and determine the “symptom free time” achieved with each therapeutic approach. In addition we will assess the cost-effectiveness of AL compared with PUVA at short term and longer term. Patients will be asked to complete questionnaires relating to their quality of life, health care use and productivity costs, how much they have benefitted from the treatment, and the usefulness of the education and support received. A further aim of the study will be to explore treatment effects in different hand eczema subgroups. Results obtained in this study will improve the treatment pathways for patients suffering from severe HE and will influence guidelines on the long term management of this frequent disease.

Research activity codes: 6.1 PHARMACEUTICALS;6.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: SKIN