Elsevier

The Lancet

Volume 389, Issue 10086, 10–16 June 2017, Pages 2287-2303
The Lancet

Articles
Long-term management of moderate-to-severe atopic dermatitis with dupilumab and concomitant topical corticosteroids (LIBERTY AD CHRONOS): a 1-year, randomised, double-blinded, placebo-controlled, phase 3 trial

https://doi.org/10.1016/S0140-6736(17)31191-1Get rights and content

Summary

Background

Dupilumab (an anti-interleukin-4-receptor-α monoclonal antibody) blocks signalling of interleukin 4 and interleukin 13, type 2/Th2 cytokines implicated in numerous allergic diseases ranging from asthma to atopic dermatitis. Previous 16-week monotherapy studies showed that dupilumab substantially improved signs and symptoms of moderate-to-severe atopic dermatitis with acceptable safety, validating the crucial role of interleukin 4 and interleukin 13 in atopic dermatitis pathogenesis. We aimed to evaluate the long-term efficacy and safety of dupilumab with medium-potency topical corticosteroids versus placebo with topical corticosteroids in adults with moderate-to-severe atopic dermatitis.

Methods

In this 1-year, randomised, double-blinded, placebo-controlled, phase 3 study (LIBERTY AD CHRONOS), adults with moderate-to-severe atopic dermatitis and inadequate response to topical corticosteroids were enrolled at 161 hospitals, clinics, and academic institutions in 14 countries in Europe, Asia-Pacific, and North America. Patients were randomly assigned (3:1:3) to subcutaneous dupilumab 300 mg once weekly (qw), dupilumab 300 mg every 2 weeks (q2w), or placebo via a central interactive voice/web response system, stratified by severity and global region. All three groups were given concomitant topical corticosteroids with or without topical calcineurin inhibitors where inadvisable for topical corticosteroids. Topical corticosteroids could be tapered, stopped, or restarted on the basis of disease activity. Coprimary endpoints were patients (%) achieving Investigator's Global Assessment (IGA) 0/1 and 2-point or higher improvement from baseline, and Eczema Area and Severity Index 75% improvement from baseline (EASI-75) at week 16. Week 16 efficacy and week 52 safety analyses included all randomised patients; week 52 efficacy included patients who completed treatment by US regulatory submission cutoff. This study is registered with ClinicalTrials.gov, NCT02260986.

Findings

Between Oct 3, 2014, and July 31, 2015, 740 patients were enrolled: 319 were randomly assigned to dupilumab qw plus topical corticosteroids, 106 to dupilumab q2w plus topical corticosteroids, and 315 to placebo plus topical corticosteroids. 623 (270, 89, and 264, respectively) were evaluable for week 52 efficacy. At week 16, more patients who received dupilumab plus topical corticosteroids achieved the coprimary endpoints of IGA 0/1 (39% [125 patients] who received dupilumab plus topical corticosteroids qw and 39% [41 patients] who received dupilumab q2w plus topical corticosteroids vs 12% [39 patients] who received placebo plus topical corticosteroids; p<0·0001) and EASI-75 (64% [204] and 69% [73] vs 23% [73]; p<0·0001). Week 52 results were similar. Adverse events were reported in 261 (83%) patients who received dupilumab qw plus topical corticosteroids, 97 (88%) patients who received dupilumab q2w, and 266 (84%) patients who received placebo, and serious adverse events in nine (3%), four (4%), and 16 (5%) patients, respectively. No significant dupilumab-induced laboratory abnormalities were noted. Injection-site reactions and conjunctivitis were more common in patients treated with dupilumab plus topical corticosteroids-treated patients than in patients treated with placebo plus topical corticosteroids.

Interpretation

Dupilumab added to standard topical corticosteroid treatment for 1 year improved atopic dermatitis signs and symptoms, with acceptable safety.

Funding

Sanofi and Regeneron Pharmaceuticals Inc.

Introduction

Atopic dermatitis is a chronic, relapsing inflammatory skin disorder characterised by intense pruritus and excoriations, with erythematous, xerotic, lichenified, fissured skin, and increased risk of skin infections.1, 2, 3 Atopic dermatitis affects 2–10% of adults worldwide, and in severe cases is associated with substantial psychosocial distress and systemic comorbidities.4, 5 As a chronic disease, moderate-to-severe atopic dermatitis often requires long-term treatment; however, data for efficacy and safety of long-term treatment with systemic immunosuppressive medications are limited.6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 Treatment guidelines recommend limiting treatment with high-potency topical corticosteroids with or without topical calcineurin inhibitors to a short period for acute atopic dermatitis flares uncontrolled by moisturisers and general skin care.14, 15, 17, 18, 19 Systemic treatments, including corticosteroids and immunosuppressants (eg, ciclosporin, methotrexate, or azathioprine) or phototherapy are only recommended when atopic dermatitis is not controlled by topical medications or when topical corticosteroids cannot be tapered to safe maintenance levels.14, 15, 16, 17, 18, 19, 20 Neither continuous use of high-potency topical corticosteroids nor systemic treatments are suitable for long-term treatment due to an unfavourable benefit-to-risk profile.14, 15, 16, 17, 18, 19, 20 Therefore, there is a high unmet need for safe and effective long-term therapies for moderate-to-severe atopic dermatitis.

Research in context

Evidence before this study

Long-term treatment options are limited for patients with moderate-to-severe atopic dermatitis refractory to topical therapy. Long-term use of systemic corticosteroids and other systemic immunosuppressants is not recommended, due to risk of serious toxicities. Dupilumab is a fully human monoclonal antibody that binds specifically to the shared α chain subunit of the interleukin-4 and interleukin-13 receptors, thereby inhibiting the signalling of interleukin 4 and interleukin 13. Dupilumab showed efficacy and acceptable safety in randomised, placebo-controlled, double-blind early-phase studies of dupilumab monotherapy for 4 weeks or 12 weeks, and with concomitant topical corticosteroids for 4 weeks, and as monotherapy for 16 weeks in phase 2b and phase 3 studies in patients with moderate-to-severe atopic dermatitis. To identify randomised, controlled, blinded clinical trials of long-term (>16 weeks) systemic treatment in atopic dermatitis, we searched PubMed using the search terms: “atopic dermatitis”, “eczema”, “systemic”, “cyclosporine”, “ciclosporin”, “methotrexate”, “azathioprine”, “mycophenolate”, “methylprednisolone”, “dexamethasone”, “prednisolone”, “prednisone”, “corticosteroids”, “glucocorticoids”, “antibody”, “clinical trial”, and “human”, published from Jan 1, 1995, to Jan 25, 2017. We identified four randomised, controlled long-term studies of ciclosporin with or without topical treatments. No other randomised, controlled studies of long-term systemic treatment were identified, and thus neither a meta-analysis nor a systemic review was done.

Added value of this study

LIBERTY AD CHRONOS is the first long-term, placebo-controlled, double-blinded study with dupilumab that allowed for the concomitant use of medium-potency or low-potency topical corticosteroids with or without topical calcineurin inhibitors as background therapy in patients with moderate-to-severe atopic dermatitis and inadequate response to topical medications. Patients were randomly assigned (3:1:3) to dupilumab 300 mg weekly, dupilumab 300 mg every 2 weeks, or placebo weekly; all patients used concomitant topical corticosteroids with or without topical calcineurin inhibitors, which could be tapered or stopped and restarted depending on need, or topical calcineurin inhibitors where inadvisable for topical corticosteroids. Our results show significant benefit of adding dupilumab to topical corticosteroids with or without topical calcineurin inhibitors over a broad range of efficacy outcomes. Both dupilumab plus topical corticosteroids dose groups, compared with placebo plus topical corticosteroids, improved multiple measures of clinical severity, reduced rates of atopic dermatitis flares, and improved pruritus and other patient-reported symptoms of atopic dermatitis, symptoms of depression and anxiety, and quality of life. Dupilumab plus topical corticosteroids had an acceptable safety profile with no clinically meaningful differences in laboratory values. No new safety signals were identified in this study, showing no additional safety concerns resulting from concomitant topical corticosteroids with or without topical calcineurin inhibitors with dupilumab.

Implications of all the available evidence

In view of the chronicity and dynamic nature of atopic dermatitis and the resulting need for long-term treatment, the 1-year safety and efficacy outcomes of this study provide critical evidence for assessment of the benefit-to-risk profile of dupilumab for long-term management of moderate-to-severe atopic dermatitis not adequately controlled with topical corticosteroids with or without topical calcineurin inhibitors alone. Dupilumab added to a background of concomitant topical medications improved multiple aspects of clinical and patient-reported outcomes considered to be crucial to positively modify the natural history of moderate-to-severe atopic dermatitis. Because these topical medications are a mainstay of treatment for moderate-to-severe atopic dermatitis per current treatment guidelines, their concomitant use (as needed) in this study closely mimics real-world treatment protocols and might provide relevant guidance on the use of a biological background therapy in adults with moderate-to-severe atopic dermatitis.

Dupilumab is a fully human monoclonal antibody that binds specifically to the shared α chain subunit of the interleukin-4 and interleukin-13 receptors (interleukin-4R-α), inhibiting the signalling of interleukin 4 and interleukin 13, type 2/Th2 inflammatory cytokines implicated in numerous allergic diseases ranging from asthma to atopic dermatitis.21 In its first pivotal study in asthma, dupilumab showed substantial improvement in lung function assessed by forced expiratory volume in 1 s (FEV1) as well as 71–81% reduction in exacerbations,22 while a phase 2 study in nasal polyposis with chronic rhinosinusitis also robustly satisfied all its primary endpoints.23 Similarly, both in early-phase, randomised, placebo-controlled studies in which dupilumab was given either as monotherapy or concomitantly with topical corticosteroids,24, 25, 26 as well as in two larger phase 3 studies in which dupilumab monotherapy was compared with placebo at 16 weeks in patients with moderate-to-severe atopic dermatitis and inadequate response to topical medications,27 dupilumab resulted in clinically and significant improvements in clinical signs and symptoms of atopic dermatitis, with an acceptable safety profile. These clinical studies validate the crucial role of interleukin 4 and interleukin 13 in multiple allergic (type 2 immune) disease settings, and particularly in atopic dermatitis. Dupilumab has been approved by the US Food and Drug Administration (FDA) for use in adult patients with moderate-to-severe atopic dermatitis whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable.

We aimed to assess efficacy and safety of 52 weeks of continuous treatment with two dose regimens of dupilumab with background therapy of concomitant medium-potency or low-potency topical corticosteroids with or without topical calcineurin inhibitors, in comparison to topical corticosteroids with or without topical calcineurin inhibitor treatment, in adults with moderate-to-severe atopic dermatitis who had a previously documented inadequate response to topical medication (topical corticosteroids with or without topical calcineurin inhibitors) or systemic treatment. Concomitant topical corticosteroids with or without topical calcineurin inhibitors could be tapered, stopped, or restarted as clinically required during the study. Efficacy at week 16 was the primary objective; key secondary objectives were safety and efficacy over the 52-week treatment period.

Section snippets

Study design and participants

This 1-year randomised, placebo-controlled, double-blind, multicentre, parallel-group phase 3 study (LIBERTY AD CHRONOS) was done at 161 sites (hospitals, clinics, and academic institutions) in Australia, Canada, Czech Republic, Hungary, Italy, Japan, the Netherlands, New Zealand, Poland, Romania, South Korea, Spain, the UK, and the USA (appendix pp 3–6).

Key inclusion criteria included age 18 years or older; atopic dermatitis (American Academy of Dermatology Consensus Criteria3) present for 3

Results

Between Oct 3, 2014, and July 31, 2015, 740 patients were enrolled; 319 were randomly assigned to dupilumab 300 mg qw plus topical corticosteroids, 106 to dupilumab 300 mg q2w plus topical corticosteroids, and 315 to placebo plus topical corticosteroids, respectively (figure 1). Four patients who were originally randomised to the dupilumab qw plus topical corticosteroids group had at least three fewer dupilumab injections than planned through week 16, and therefore were analysed under the

Discussion

This 1-year study of dupilumab with concomitant topical medications is the first large, randomised, double-blinded, placebo-controlled study of long-term systemic treatment in patients with moderate-to-severe atopic dermatitis. Both dose regimens of dupilumab plus topical corticosteroids, when compared with placebo plus topical corticosteroids, improved atopic dermatitis lesions as assessed by IGA 0/1 response and EASI-75 at week 16 (coprimary endpoints). The improvement was sustained over the

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