Background

Systemic therapies are typically combined with topical corticosteroids for the management of moderate-to-severe atopic dermatitis. Upadacitinib is an oral Janus kinase (JAK) inhibitor with greater inhibitory potency for JAK1 than JAK2, JAK3, or tyrosine kinase 2 that is being tested for atopic dermatitis. We aimed to assess the efficacy and safety of upadacitinib plus topical corticosteroids compared with placebo for the treatment of moderate-to-severe atopic dermatitis.

Methods

In this randomised, double-blind, placebo-controlled, phase 3 trial (AD Up) adults (aged 18–75 years) and adolescents (aged 12–17 years) with chronic atopic dermatitis that was moderate to severe (≥10% of body surface area affected, Eczema Area and Severity Index [EASI] score of ≥16, validated Investigator's Global Assessment for atopic dermatitis [vIGA-AD] score of ≥3, and weekly average Worst Pruritus Numerical Rating Scale score of ≥4 at baseline) were enrolled at 171 clinical centres across 22 countries in the Asia-Pacific region, Europe, the Middle East, North America, and Oceania. Patients were randomly assigned (1:1:1) to receive upadacitinib 15 mg, upadacitinib 30 mg, or placebo once daily, all in combination with topical corticosteroids for 16 weeks. Randomisation was done using an interactive response technology system, stratified by baseline disease severity, geographical region, and age. Study investigators, study site personnel, and patients were masked to study treatment. The coprimary endpoints were the proportion of patients who had achieved at least a 75% reduction in EASI score from baseline (EASI-75) and the proportion of patients who had achieved a vIGA-AD response (defined as a vIGA-AD score of 0 [clear] or 1 [almost clear] with ≥2 grades of improvement from baseline) at week 16. Efficacy was analysed in the intention-to-treat population and safety was analysed in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT03568318, and is active, but not recruiting.

Findings

Between Aug 9, 2018, and Dec 20, 2019, 901 patients were randomly assigned to receive upadacitinib 15 mg plus topical corticosteroids (n=300), upadacitinib 30 mg plus topical corticosteroids (n=297), or placebo plus topical corticosteroids (n=304). At week 16, the proportion of patients who had achieved EASI-75 was significantly higher in the upadacitinib 15 mg plus topical corticosteroid group (194 [65%] of 300 patients) and the upadacitinib 30 mg plus topical corticosteroids group (229 [77%] of 297 patients) than the placebo group (80 [26%] of 304 patients; adjusted difference in EASI-75 response rate vs placebo, 38·1% [95% CI 30·8–45·4] for the upadacitinib 15 mg group and 50·6% [43·8–57·4] for the upadacitinib 30 mg group; p<0·0001 for both doses). The proportion of patients who had achieved a vIGA-AD response at week 16 was significantly higher in the upadacitinib 15 mg plus topical corticosteroid group (119 [40%] patients) and upadacitinib 30 mg plus topical corticosteroid group (174 [59%] patients) than the placebo group (33 [11%] patients; adjusted difference in vIGA-AD response vs placebo, 28·5% [22·1–34·9] for the upadacitinib 15 mg group and 47·6% [41·1–54·0] for the upadacitinib 30 mg group; p<0·0001 for both doses). During the double-blind period, upadacitinib 15 and 30 mg were well tolerated in combination with topical corticosteroids. The most frequently reported treatment-emergent adverse events (≥5% in any treatment group) were acne, nasopharyngitis, upper respiratory tract infection, oral herpes, elevation of blood creatine phosphokinase levels, headache, and atopic dermatitis. The incidence of acne was higher in the upadacitinib 15 mg (30 [10%] of 300 patients) and upadacitinib 30 mg (41 [14%] of 297 patients) groups than the placebo group (six [2%] of 304 patients). The incidence of adverse events leading to discontinuation of study drug (four [1%] patients in the upadacitinib 15 mg plus topical corticosteroids group, four [1%] patients in the upadacitinib 30 mg plus topical corticosteroids group, and seven [2%] patients in the placebo plus topical corticosteroids group) and serious adverse events (seven [2%] patients, four [1%] patients, and nine [3%] patients) were similar among treatment groups. No deaths were reported in any treatment group.

Interpretation

Upadacitinib plus topical corticosteroids was well tolerated and superior to placebo plus topical corticosteroids. Upadacitinib as combination therapy had a positive benefit–risk profile in adults and adolescents with moderate-to-severe atopic dermatitis.

Funding

AbbVie.

中文翻译：

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upadacitinib 联合局部皮质类固醇治疗青少年和成人中重度特应性皮炎 (AD Up) 的安全性和有效性：随机、双盲、安慰剂对照、3 期试验的结果

背景

全身治疗通常与局部皮质类固醇联合用于治疗中度至重度特应性皮炎。 Upadacitinib 是一种口服 Janus 激酶 (JAK) 抑制剂，对 JAK1 的抑制效力高于正在测试特应性皮炎的 JAK2、JAK3 或酪氨酸激酶 2。我们旨在评估 upadacitinib 加局部皮质类固醇与安慰剂相比治疗中至重度特应性皮炎的疗效和安全性。

方法

在这项随机、双盲、安慰剂对照、3 期试验 (AD Up) 中，患有中度至重度慢性特应性皮炎的成人（18-75 岁）和青少年（12-17 岁）（≥10%体表面积受影响，湿疹面积和严重程度指数 [EASI] 评分 ≥ 16，经验证的特应性皮炎调查员总体评估 [vIGA-AD] 评分≥3，以及基线时每周平均最严重瘙痒数值评定量表评分≥4）在亚太地区、欧洲、中东、北美和大洋洲的 22 个国家的 171 个临床中心入组。患者被随机分配 (1:1:1) 每天一次接受 upadacitinib 15 mg、upadacitinib 30 mg 或安慰剂，所有这些都与局部皮质类固醇联合治疗 16 周。随机化是使用交互式响应技术系统完成的，按基线疾病严重程度、地理区域和年龄分层。研究调查员、研究中心工作人员和患者对研究治疗不知情。共同主要终点是 EASI 评分从基线 (EASI-75) 降低至少 75% 的患者比例和达到 vIGA-AD 反应的患者比例（定义为 vIGA-AD 评分为 0 [清除] 或 1 [几乎清除] 与基线相比有 ≥ 2 级改善）在第 16 周。在意向治疗人群中分析了疗效，并在所有接受至少一剂研究药物的患者中分析了安全性。该研究已在 ClinicalTrials.gov 注册，NCT03568318，并且是活跃的，但不招募。并且患者被蒙蔽以研究治疗。共同主要终点是 EASI 评分从基线 (EASI-75) 降低至少 75% 的患者比例和达到 vIGA-AD 反应的患者比例（定义为 vIGA-AD 评分为 0 [清除] 或 1 [几乎清除] 与基线相比有 ≥ 2 级改善）在第 16 周。在意向治疗人群中分析了疗效，并在所有接受至少一剂研究药物的患者中分析了安全性。该研究已在 ClinicalTrials.gov 注册，NCT03568318，并且是活跃的，但不招募。并且患者被蒙蔽以研究治疗。共同主要终点是 EASI 评分从基线 (EASI-75) 降低至少 75% 的患者比例和达到 vIGA-AD 反应的患者比例（定义为 vIGA-AD 评分为 0 [清除] 或 1 [几乎清除] 与基线相比有 ≥ 2 级改善）在第 16 周。在意向治疗人群中分析了疗效，并在所有接受至少一剂研究药物的患者中分析了安全性。该研究已在 ClinicalTrials.gov 注册，NCT03568318，并且是活跃的，但不招募。共同主要终点是 EASI 评分从基线 (EASI-75) 降低至少 75% 的患者比例和达到 vIGA-AD 反应的患者比例（定义为 vIGA-AD 评分为 0 [清除] 或 1 [几乎清除] 与基线相比有 ≥ 2 级改善）在第 16 周。在意向治疗人群中分析了疗效，并在所有接受至少一剂研究药物的患者中分析了安全性。该研究已在 ClinicalTrials.gov 注册，NCT03568318，并且是活跃的，但不招募。共同主要终点是 EASI 评分从基线 (EASI-75) 降低至少 75% 的患者比例和达到 vIGA-AD 反应的患者比例（定义为 vIGA-AD 评分为 0 [清除] 或 1 [几乎清除] 与基线相比有 ≥ 2 级改善）在第 16 周。在意向治疗人群中分析了疗效，并在所有接受至少一剂研究药物的患者中分析了安全性。该研究已在 ClinicalTrials.gov 注册，NCT03568318，并且是活跃的，但不招募。

发现

2018 年 8 月 9 日至 2019 年 12 月 20 日期间，901 名患者被随机分配接受 upadacitinib 15 mg 加局部皮质类固醇（n = 300）、upadacitinib 30 mg 加局部皮质类固醇（n = 297）或安慰剂加局部皮质类固醇（n =304）。在第 16 周，达到 EASI-75 的患者比例在 upadacitinib 15 mg 加局部皮质类固醇组（300 名患者中的 194 [65%]）和 upadacitinib 30 mg 加局部皮质类固醇组（229 [77%] ] 297 名患者）比安慰剂组（304 名患者中的 80 名 [26%]；调整后的 EASI-75 反应率与安慰剂，upadacitinib 15 mg 组为 38·1% [95% CI 30·8-45·4]，upadacitinib 30 mg 组为 50·6% [43·8-57·4]；对于两种剂量，p<0·0001)。在 upadacitinib 15 mg 加外用皮质类固醇组（119 [40%] 名患者）和 upadacitinib 30 mg 加外用皮质类固醇组（174 [59%] 名患者）中，第 16 周达到 vIGA-AD 反应的患者比例显着更高) 比安慰剂组（33 [11%] 名患者；调整后的 vIGA-AD 反应与安慰剂，upadacitinib 15 mg 组为 28·5% [22·1-34·9]，upadacitinib 30 mg 组为 47·6% [41·1-54·0]；对于两种剂量，p<0·0001)。在双盲期间，upadacitinib 15 和 30 mg 与局部皮质类固醇联合使用的耐受性良好。最常报告的治疗出现的不良事件（任何治疗组中≥5%）是痤疮、鼻咽炎、上呼吸道感染、口腔疱疹、血肌酸磷酸激酶水平升高、头痛和特应性皮炎。upadacitinib 15 mg（300 名患者中的 30 [10%]）和 upadacitinib 30 mg（297 名患者中的 41 [14%]）组的痤疮发生率高于安慰剂组（304 名患者中的 6 [2%]） . 导致停用研究药物的不良事件发生率（upadacitinib 15 mg 加局部皮质类固醇组中有四名 [1%] 患者，upadacitinib 30 mg 加局部皮质类固醇组中有四名 [1%] 患者，以及七名 [2%] 患者）安慰剂加局部皮质类固醇组的患者）和严重不良事件（7 [2%] 名患者、4 名 [1%] 患者和 9 名 [3%] 患者）在治疗组之间相似。在任何治疗组中均未报告死亡。

解释

Upadacitinib 加外用皮质类固醇耐受良好，优于安慰剂加外用皮质类固醇。Upadacitinib 作为联合疗法在患有中度至重度特应性皮炎的成人和青少年中具有积极的收益 - 风险特征。

资金

艾伯维。