A Randomized Controlled Trial Protocol Assessing the Effectiveness, Safety and Cost-effectiveness of Methotrexate vs. Ciclosporin in the Treatment of Severe Atopic Eczema in Children

The TREatment of Severe Atopic Eczema Trial (TREAT)

A.D. Irvine; A.P. Jones; P. Beattie; S. Baron; F. Browne; F. Ashoor; L. O'Neill; A. Rosala-Hallas; T. Sach; C. Spowart; L. Taams; C. Walker; M. Wan; N. Webb; P. Williamson; C. Flohr; on behalf of the TREAT Trial Investigators

Disclosures

The British Journal of Dermatology. 2018;179(6):1297-1306. 

In This Article

Abstract and Introduction

Abstract

Background: Oral systemic immunomodulatory medication is regularly used off-licence in children with severe atopic eczema. However, there is no firm evidence regarding the effectiveness, safety, cost-effectiveness and impact on quality of life from an adequately powered randomized controlled trial (RCT) using systemic medication in children.

Objectives: To assess whether there is a difference in the speed of onset, effectiveness, side-effect profile and reduction in flares post-treatment between ciclosporin (CyA) and methotrexate (MTX), and also the cost-effectiveness of the drugs. Treatment impact on quality of life will also be examined in addition to whether FLG genotype influences treatment response. In addition, the trial studies the immune–metabolic effects of CyA and MTX.

Methods: Multicentre, parallel group, assessor-blind, pragmatic RCT of 36 weeks' duration with a 24-week follow-up period. In total, 102 children aged 2–16 years with moderate-to-severe atopic eczema, unresponsive to topical treatment will be randomized (1 : 1) to receive MTX (0·4 mg kg−1 per week) or CyA (4 mg kg−1 per day).

Results: The trial has two primary outcomes: change from baseline to 12 weeks in Objective Severity Scoring of Atopic Dermatitis (o-SCORAD) and time to first significant flare following treatment cessation.

Conclusions: This trial addresses important therapeutic questions, highlighted in systematic reviews and treatment guidelines for atopic eczema. The trial design is pragmatic to reflect current clinical practice.

Introduction

Atopic eczema (synonymous with 'atopic dermatitis'), is a chronic, pruritic inflammatory skin disease, affecting around 20% of U.K. children, 16% of whom have moderate-to-severe disease.[1] It comes at a high cost, for patients and families in addition to society.[2,3] Severe atopic eczema is often accompanied by significant sleep disturbance, poor school attendance and social withdrawal, in addition to attention-deficit hyperactivity disorder, anxiety and clinical depression.[4] Skin infections are also common in poorly controlled atopic eczema and a reason for hospital admission.[4]

Although most cases of atopic eczema are adequately controlled with emollients, topical anti-inflammatory treatments and/or ultraviolet (UV) therapy, around 2% of children require oral immunosuppressive treatment to induce and maintain disease control.[5] There are, however, only limited systemic treatment options available and there is concern about their potential short- and long-term side-effects.[5] The European TREatment of severe Atopic eczema in children Taskforce survey of 765 consultant dermatologists and paediatricians from eight European countries was conducted to establish which systemic treatment options are available.[6] This showed that the first-choice systemic immunosuppressive agent was overall ciclosporin (CyA) with 43%, compared with the U.K. where 39% use azathioprine (AZA) and 35% use CyA.[6] Although methotrexate (MTX) was only the third most commonly used systemic treatment in the survey in the U.K., it is increasingly being used as a first-line systemic agent in children, as shown by our most recent treatment survey in the U.S.A.[7] Furthermore, while there is significant concern about the long-term prescribing of CyA (renal toxicity) and AZA (in particular lymphoma and progressive multifocal leucoencephalopathy), MTX is generally considered well tolerated and safe in the long term.[5,8] In addition, two randomized controlled trials (RCTs) and their follow-up studies suggested no significant difference in efficacy between MTX and AZA in adults and MTX and CyA in children, even if CyA appears to show its treatment effect more quickly.[8–11] However, these studies were statistically underpowered.[12]

There is therefore a clear need to compare MTX with the most established immunosuppressive medication, CyA, which has also been highlighted in a systematic review.[13] Both drugs have demonstrated a reduction in atopic eczema severity and improve quality of life.[4,5,14] The protocol for the trial is presented here and has been written in accordance with the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidelines.[15]

The primary objectives are to compare the safety and efficacy of MTX vs. CyA, in recalcitrant atopic eczema in children, during 36 weeks of treatment and to compare disease control post-treatment cessation. Secondary objectives are to examine: (i) the number of flares during the trial period as well disease severity throughout follow-up; (ii) the impact on quality of life; (iii) the effects of both drugs using novel systemic and cutaneous markers of inflammation during treatment; (iv) the effect of filaggrin (FLG) genotype and T-cell cytokine signatures on treatment efficacy; (v) the side-effect profiles of both drugs; and (vi) a comparison of the cost-effectiveness of both drugs in a health economic evaluation.

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