Dupilumab versus placebo in adults and adolescents with eosinophilic gastritis (DEGAS): a double-blind, placebo-controlled, phase 2, multicentre, randomised controlled trial.

Dupilumab blocks type 2 cytokines IL-4 and IL-13 and has efficacy in multiple diseases characterised by type 2 inflammation, including eosinophilic oesophagitis.

Dupilumab阻断了2型细胞因子IL-4和IL-13，并在多种以2型炎症为特征的疾病中显示出疗效，包括嗜酸性食管炎。

We aimed to assess the efficacy and safety of dupilumab in patients with eosinophilic gastritis.

我们的目标是评估 dupilumab 在嗜酸性粒细胞性胃炎患者中的疗效和安全性。

Methods

DEGAS was a proof-of-concept, phase 2, multicentre, randomised controlled trialconsisting of a 12-week, double-blind, placebo-controlledperiod, followed by a 24-week open-label extension period.

DEGAS 是一个概念验证、二期、多中心、随机对照试验，包括一个为期12周的双盲、安慰剂对照期，随后是一个为期24周的开放标签扩展期。

Patients aged 12-70 years from 11 hospitals in the USA with histologically active eosinophilic gastritis (≥30 eosinophils per high-power field [HPF] in at least five HPFs in the gastric antrum and/or body) and moderate-to-severe symptoms occurring at least 2 days per week in the 2 weeks before screening were recruited.

招募了来自美国11家医院的12至70岁患者，这些患者具有组织学活跃的嗜酸性胃炎（在胃窦和/或胃体至少五个高倍视野（HPF）中每个HPF的嗜酸性粒细胞数量≥30个）以及在筛查前2周内每周至少2天出现中度至重度症状。

Patients with current or recent use of any biologic or current use of systemic steroids at a dose of more than 10 mg/day (prednisone) were excluded.

排除了目前正在使用或最近使用过任何生物制剂的患者，或目前正在使用系统性类固醇（剂量超过每天10毫克（泼尼松））的患者。

Eligible patients were individually randomised (1:1) to parallel groups and received six injections over 12 weeks: subcutaneous dupilumab (600 mg once followed by 300 mg every 2 weeks) or subcutaneous placebo.

符合条件的患者被个别随机分配（1:1）到平行组，并在12周内接受六次注射：皮下注射度普利尤单抗（首次600毫克，随后每两周300毫克）或皮下注射安慰剂。

Randomisation was performed using a central variable block (block sizes permuted between 2 and 4), with stratification by age (12-17 years or ≥18 years) and use (yes or no) of either systemic corticosteroids, swallowed corticosteroids for eosinophilic gastritis, or non-steroidal systemic immunosuppression therapy.

使用中央可变区块（区块大小在2到4之间置换）进行随机化，按年龄（12-17岁或≥18岁）和使用（是或否）系统性皮质类固醇、用于嗜酸性胃炎的口服皮质类固醇或非皮质类固醇系统性免疫抑制治疗进行分层。

Throughout the duration of the study, patients were expected to maintain their treatments or diets for eosinophilic gastritis.

在整个研究期间，患者被期望维持他们的治疗或饮食以治疗嗜酸性胃炎。

All patients who completed the double-blindperiod could enter the open-label extension at week 12, during which both groups received dupilumab until week 34.

所有完成双盲期的患者都可以在第12周进入开放标签扩展期，在此期间，两组患者均接受dupilumab治疗，直至第34周。

The primary endpoint of relative change from baseline in mean gastric eosinophil count from the five most eosinophil-dense HPFs in the gastric antrum and/or body was analysed at week 12 using linear regression.

主要终点是从基线开始胃窦和/或胃体中五个最密集嗜酸性粒细胞的高倍视野（HPFs）的平均胃嗜酸性粒细胞计数的相对变化，在第12周使用线性回归进行分析。

Secondary endpoints included absolute changes from baseline in Eosinophilic Gastritis Histologic Scoring System (EoS-HSS) total score, mean gastric eosinophil count from the five most eosinophil-dense HPFs, and Eosinophilic Gastritis Endoscopic Reference System (EoG-REFS) total score.

次要终点包括从基线开始的嗜酸性粒细胞性胃炎组织学评分系统（EoS-HSS）总分、五个最密集嗜酸性粒细胞的高倍视野（HPFs）的平均胃嗜酸性粒细胞计数以及嗜酸性粒细胞性胃炎内镜参考系统（EoG-REFS）总分的绝对变化。

All randomly assigned patients who received at least one dose of study drug were included in the safety analysis and efficacy analyses were done in all randomly assigned patients who received at least one dose of study drug and had outcome data available at week 12 (complete case).

所有接受至少一次研究药物的随机分配患者均被纳入安全性分析，所有接受至少一次研究药物且在第12周有结果数据的随机分配患者（完整案例）均进行了疗效分析。

This study is registered with ClinicalTrials.gov (NCT03678545) and is now complete.

该研究已在ClinicalTrials.gov注册（NCT03678545），目前研究已完成。

Results

Between May 14, 2021, and Nov 10, 2023, we randomly assigned 41 patients, of whom 21 (51%) received dupilumab and 20 (49%) received placebo during the double-blindperiod and were included in the safety analysis.

在2021年5月14日至2023年11月10日期间，我们随机分配了41名患者，其中21名（51%）在双盲期间接受了dupilumab治疗，20名（49%）接受了安慰剂治疗，并被纳入安全性分析。

Patients were aged 12-59 years (mean 30·5 years [SD 13·2]; seven [17%] aged <18 years), 37 (90%) were White, one (2%) was Asian, one (2%) was Black or African American, two (5%) were of multiple races, 25 (61%) were female, and 16 (39%) were male.

患者年龄在12至59岁之间（平均30.5岁，标准差13.2；17%的患者年龄小于18岁），其中37名（90%）为白人，1名（2%）为亚洲人，1名（2%）为黑人或非裔美国人，2名（5%）为多种族，25名（61%）为女性，16名（39%）为男性。

One patient from the placebo group withdrew before week 12; the remaining 21 patients treated with dupilumab and 19 patients treated with placebo had available data and were assessed for the primary endpoint.

安慰剂组有一名患者在第12周前退出；剩余的21名接受度普利尤单抗治疗的患者和19名接受安慰剂治疗的患者有可用数据，并被评估为主要终点。

At week 12, the relative reduction in the primary endpoint was greater with dupilumab (estimated mean change -50% [95% CI -66 to -34]) than with placebo (-4% [-20 to 13]; difference -47 percentage points [-70 to -24]; p<0·0001).

在第12周时，主要终点的相对减少度普利尤单抗治疗组更大（估计平均变化-50% [95% 置信区间-66至-34]）相比于安慰剂组（-4% [-20至13]；差异-47个百分点 [-70至-24]；p<0·0001）。

Significant differences between groups were noted for the secondary endpoints of absolute change from baseline in EoS-HSS total score (difference -0·10 [95% CI -0·18 to -0·03]; p=0·0055), absolute change from baseline in mean gastric eosinophil count (-38·8 [-75·6 to -17·8]; p=0·0008), and absolute change from baseline in EoG-REFS total score (-3·42 [-6·18 to -0·65]; p=0·016).

在次要终点方面，两组间在EoS-HSS总分从基线的绝对变化（差异-0.10 [95% 置信区间 -0.18至-0.03]；p=0.0055）、胃部嗜酸性粒细胞平均计数从基线的绝对变化（-38.8 [-75.6至-17.8]；p=0.0008）以及EoG-REFS总分从基线的绝对变化（-3.42 [-6.18至-0.65]；p=0.016）上存在显著差异。

At week 12, the incidenceof treatment-emergent adverse events was similar between dupilumab (17 [81%]) and placebo (17 [85%]).

在第12周时，dupilumab（17 [81%]）和安慰剂（17 [85%]）之间治疗后新发不良事件的发生率相似。

The most common adverse eventwas blood eosinophilia, with similar incidencein the dupilumab (six [29%]) and placebo (six [30%]) groups.

最常见的不良事件是血液嗜酸性粒细胞增多，杜普利尤单抗组（六例[29%]）和安慰剂组（六例[30%]）的发生率相似。

No serious adverse events or treatment-related deaths were reported.

没有报告严重的不良事件或与治疗相关的死亡事件。

interpretation

The improvement of histological outcomes of eosinophilic gastritis with dupilumab in this proof-of-concept study shows type 2 inflammatory involvement in the disease and the potential value of dupilumab for the treatment of eosinophilic gastritis.

这项概念验证研究显示，使用 dupilumab 可以改善嗜酸性粒细胞性胃炎的组织学结果，表明疾病中涉及2型炎症，并且 dupilumab 治疗嗜酸性粒细胞性胃炎具有潜在价值。

funding

National Institutes of Health, USA; Regeneron Pharmaceuticals Inc; and Sanofi.

美国国立卫生研究院；再生元制药公司；以及赛诺菲。