Dupilumab in children aged 6 months to younger than 6 years with uncontrolled atopic dermatitis: a randomised, double-blind, placebo-controlled, phase 3 trial,The Lancet

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Dupilumab in children aged 6 months to younger than 6 years with uncontrolled atopic dermatitis: a randomised, double-blind, placebo-controlled, phase 3 trial
The Lancet ( IF 98.4 ) Pub Date : 2022-09-15 , DOI: 10.1016/s0140-6736(22)01539-2
Amy S Paller ₁ , Eric L Simpson ₂ , Elaine C Siegfried ₃ , Michael J Cork ₄ , Andreas Wollenberg ₅ , Peter D Arkwright ₆ , Weily Soong ₇ , Mercedes E Gonzalez ₈ , Lynda C Schneider ₉ , Robert Sidbury ₁₀ , Benjamin Lockshin ₁₁ , Steven Meltzer ₁₂ , Zhixiao Wang ₁₃ , Leda P Mannent ₁₄ , Nikhil Amin ₁₃ , Yiping Sun ₁₃ , Elizabeth Laws ₁₅ , Bolanle Akinlade ₁₃ , Myles Dillon ₁₃ , Matthew P Kosloski ₁₃ , Mohamed A Kamal ₁₃ , Ariane Dubost-Brama ₁₄ , Naimish Patel ₁₆ , David M Weinreich ₁₃ , George D Yancopoulos ₁₃ , John T O'Malley ₁₆ , Ashish Bansal ₁₃ ,

Affiliation

Feinberg School of Medicine, Northwestern University, Chicago, IL, USA; Department of Dermatology, Ann and Robert H Lurie Children's Hospital, Chicago, IL, USA.
Department of Dermatology, Oregon Health and Science University, Portland, OR, USA.
Department of Pediatrics, Saint Louis University, St Louis, MO, USA; Department of Pediatric Dermatology, Cardinal Glennon Children's Hospital, St Louis, MO, USA.
Sheffield Dermatology Research, University of Sheffield, Sheffield, UK.
Department of Dermatology and Allergology, University Hospital, Ludwig-Maximilian University, Munich, Germany; Vrije Universiteit Brussel, Universitair Ziekenhuis Brussel, Brussels, Belgium.
Lydia Becker Institute of Immunology & Inflammation, University of Manchester, Manchester, UK.
AllerVie Health, Alabama Allergy & Asthma Center, Birmingham, AL, USA.
The Phillip Frost Department of Dermatology, University of Miami Miller School of Medicine, Miami, FL, USA.
Department of Pediatrics, Boston Children's Hospital, Boston, MA, USA.
Department of Pediatrics, Seattle Children's Hospital, Seattle, WA, USA.
US Dermatology Partners, Rockville, MD, USA.
Beach Allergy and Asthma Specialty Group, Long Beach, CA, USA.
Regeneron Pharmaceuticals, Tarrytown, NY, USA.
Sanofi, Chilly-Mazarin, France.
Sanofi, Bridgewater, NJ, USA.
Sanofi, Cambridge, MA, USA.

Background

Current systemic treatments for children younger than 6 years with moderate-to-severe atopic dermatitis that is uncontrolled with topical therapies might have suboptimal efficacy and safety. Dupilumab is approved for older children and adults with atopic dermatitis and for other type 2 inflammatory conditions. We aimed to evaluate efficacy and safety of dupilumab with concomitant low-potency topical corticosteroids in children aged 6 months to younger than 6 years with moderate-to-severe atopic dermatitis.

Methods

This randomised, double-blind, placebo-controlled, parallel-group, phase 3 trial was conducted in 31 hospitals, clinics, and academic institutions in Europe and North America. Eligible patients were aged 6 months to younger than 6 years, with moderate-to-severe atopic dermatitis (Investigator's Global Assessment [IGA] score 3–4) diagnosed according to consensus criteria of the American Academy of Dermatology, and an inadequate response to topical corticosteroids. Patients were randomly assigned (1:1) to subcutaneous placebo or dupilumab (bodyweight ≥5 kg to <15 kg: 200 mg; bodyweight ≥15 kg to <30 kg: 300 mg) every 4 weeks plus low-potency topical corticosteroids (hydrocortisone acetate 1% cream) for 16 weeks. Randomisation was stratified by age, baseline bodyweight, and region. Patient allocation was done via a central interactive web response system, and treatment allocation was masked. The primary endpoint at week 16 was the proportion of patients with IGA score 0–1 (clear or almost clear skin). The key secondary endpoint (coprimary endpoint for the EU and EU reference market) at week 16 was the proportion of patients with at least a 75% improvement from baseline in Eczema Area and Severity Index (EASI-75). Primary analyses were done in the full analysis set (ie, all randomly assigned patients, as randomly assigned) and safety analyses were done in all patients who received any study drug. This study was registered with ClinicalTrials.gov, NCT03346434.

Findings

Between June 30, 2020, and Feb 12, 2021, 197 patients were screened for eligibility, 162 of whom were randomly assigned to receive dupilumab (n=83) or placebo (n=79) plus topical corticosteroids. At week 16, significantly more patients in the dupilumab group than in the placebo group had IGA 0–1 (23 [28%] vs three [4%], difference 24% [95% CI 13–34]; p<0·0001) and EASI-75 (44 [53%] vs eight [11%], difference 42% [95% CI 29–55]; p<0·0001). Overall prevalence of adverse events was similar in the dupilumab group (53 [64%] of 83 patients) and placebo group (58 [74%] of 78 patients). Conjunctivitis incidence was higher in the dupilumab group (four [5%]) than the placebo group (none). No dupilumab-related adverse events were serious or led to treatment discontinuation.

Interpretation

Dupilumab significantly improved atopic dermatitis signs and symptoms versus placebo in children younger than 6 years. Dupilumab was well tolerated and showed an acceptable safety profile, similar to results in older children and adults.

Funding

Sanofi and Regeneron Pharmaceuticals

中文翻译：

Dupilumab 用于 6 个月至 6 岁以下患有不受控制的特应性皮炎的儿童：一项随机、双盲、安慰剂对照的 3 期试验

背景

目前对 6 岁以下患有中度至重度特应性皮炎且局部治疗无法控制的儿童的全身治疗可能具有次优的疗效和安全性。Dupilumab 被批准用于患有特应性皮炎的年龄较大的儿童和成人以及其他 2 型炎症性疾病。我们旨在评估 dupilumab 联合低效外用皮质类固醇对 6 个月至 6 岁以下患有中度至重度特应性皮炎的儿童的疗效和安全性。

方法

这项随机、双盲、安慰剂对照、平行组、3 期试验在欧洲和北美的 31 家医院、诊所和学术机构进行。符合条件的患者年龄在 6 个月至 6 岁以下，根据美国皮肤病学会的共识标准诊断为中度至重度特应性皮炎（研究者的全球评估 [IGA] 评分 3-4），并且对局部治疗反应不足皮质类固醇。患者被随机分配 (1:1) 至皮下注射安慰剂或 dupilumab（体重≥5 kg 至 <15 kg：200 mg；体重≥15 kg 至 <30 kg：300 mg），每 4 周加低效外用皮质类固醇（氢化可的松醋酸盐 1% 乳膏）16 周。随机化按年龄、基线体重和地区进行分层。患者分配是通过中央交互式网络响应系统完成的，治疗分配被掩盖。第 16 周的主要终点是 IGA 评分为 0-1 的患者比例（皮肤透明或几乎透明）。第 16 周的关键次要终点（欧盟和欧盟参考市场的共同主要终点）是湿疹面积和严重程度指数（EASI-75）较基线改善至少 75% 的患者比例。主要分析在完整分析组（即所有随机分配的患者，随机分配）中进行，安全性分析在接受任何研究药物的所有患者中进行。该研究已在 ClinicalTrials.gov 注册，NCT03346434。第 16 周的关键次要终点（欧盟和欧盟参考市场的共同主要终点）是湿疹面积和严重程度指数（EASI-75）较基线改善至少 75% 的患者比例。主要分析在完整分析组（即所有随机分配的患者，随机分配）中进行，安全性分析在接受任何研究药物的所有患者中进行。该研究已在 ClinicalTrials.gov 注册，NCT03346434。第 16 周的关键次要终点（欧盟和欧盟参考市场的共同主要终点）是湿疹面积和严重程度指数（EASI-75）较基线改善至少 75% 的患者比例。主要分析在完整分析组（即所有随机分配的患者，随机分配）中进行，安全性分析在接受任何研究药物的所有患者中进行。该研究已在 ClinicalTrials.gov 注册，NCT03346434。随机分配）并对所有接受任何研究药物的患者进行安全性分析。该研究已在 ClinicalTrials.gov 注册，NCT03346434。随机分配）并对所有接受任何研究药物的患者进行安全性分析。该研究已在 ClinicalTrials.gov 注册，NCT03346434。

发现

在 2020 年 6 月 30 日至 2021 年 2 月 12 日期间，筛选了 197 名患者的资格，其中 162 人被随机分配接受 dupilumab（n=83）或安慰剂（n=79）加外用皮质类固醇。在第 16 周，dupilumab 组的 IGA 0-1 患者显着多于安慰剂组（23 [28%] vs 3 [4%]，差异 24% [95% CI 13-34]；p<0· 0001）和 EASI-75（44 [53%]对8 [11%]，差异 42% [95% CI 29–55]；p<0·0001）。dupilumab 组（83 名患者中的 53 名 [64%]）和安慰剂组（78 名患者中的 58 名 [74%]）的不良事件总体发生率相似。dupilumab 组的结膜炎发病率（4 [5%]）高于安慰剂组（无）。没有与 dupilumab 相关的不良事件是严重的或导致治疗中止。