Clinical Trial 2

项目总结(临床试验2) 嗜酸性胃炎(EG)是一种未被充分认识的罕见疾病，其特征是嗜酸性粒细胞聚集在 胃部不适，并与各种症状有关，包括疼痛、呕吐、体重减轻和贫血。那里 没有美国食品和药物管理局(FDA)批准的治疗EG或任何其他嗜酸性胃肠道疾病的药物 疾病(EGID)。目前，EG的治疗主要集中在饮食消除疗法上，全身 皮质类固醇，吞服局部皮质类固醇，或多种疗法的组合。尽管这些治疗方法可以 要有效，有相当大的无应答率。此外，这些疗法需要持续不断的 使用，因为大多数患者如果不维持治疗就会复发。减少饮食对健康的不利影响 生活中的个人和社会方面，因为需要避免多个共同的食物组。此外，人们的担忧 关于长期使用类固醇的风险，以及希望找到更可耐受和/或更方便的 治疗方法，推动了对其他潜在靶向治疗方法的搜索。在EG中，有更多的 胃炎性浸润物的水平，包括T细胞、嗜酸性粒细胞和肥大细胞，以及增加的 趋化因子和细胞因子，包括CCL26(嗜酸性粒细胞趋化因子-3)、白介素4(IL-4)、IL-5和IL-13。IL-5是一种直接的 嗜酸性粒细胞生长和激活因子，而IL-4和IL-13则介导变态反应的几个主要方面 炎症包括免疫球蛋白E(IgE)的产生，T细胞向2型辅助细胞(Th2)的极化， 趋化因子诱导和随后的白细胞渗透和激活，粘液产生，屏障损害， 和终末器官功能障碍。IL-4和IL-13通过一个共同的受体亚基，称为IL-4ra， 这是信号转导所必需的。DUPILUMA是一种针对IL-1的全人型单抗。 4ra，抑制IL-4和IL-13的信号传导。DUPILUMA已经证明了有效性和良好的安全性 用于患有中到重度特应性皮炎或哮喘的成人患者，最近已被批准用于特应性 皮炎是由FDA和欧洲医药机构联合开发的。这项研究的中心假设是dupiumab是 安全有效地降低嗜酸性粒细胞增多症和Th2基因图谱。为此目的， 嗜酸性胃肠道疾病研究人员(CEGIR)将进行一项原则证明、随机、 成人EG患者的安慰剂对照试验。在目标1中，我们将检验主要假设，即dupilumab将 与安慰剂治疗的患者相比，EG患者的胃嗜酸性粒细胞水平降低。在目标2中，我们将 DUPILUMA将逆转EG胃黏膜表达IL-13信号基因的假说 患者包括CDH26、CCL26和2型细胞因子基因(IL4、IL5和IL13)。预计 这项研究将提供概念证明，即EG是一种2型过敏性、免疫介导性疾病，并为 用于进一步开发和最终批准EG的治疗方法。

Project Summary (Clinical Trial 2) Eosinophilic gastritis (EG) is an understudied rare disease characterized by eosinophil accumulation in the stomach and associated with a variety of symptoms including pain, vomiting, weight loss, and anemia. There are no US Food and Drug Administration (FDA)-approved drugs for EG or any other eosinophilic gastrointestinal disease (EGID). At present, the treatment of EG has focused upon diet elimination therapy, systemic corticosteroids, swallowed topical corticosteroids, or a combination of therapies. Though these treatments can be efficacious, there are substantial rates of non-responsiveness. Moreover, these therapies require continuous use, as a majority of patients relapse if treatment is not maintained. Dietary elimination adversely impacts personal and social aspects of life owing to the need to avoid multiple common food groups. Moreover, concerns about the long-term risks of chronic steroid use, as well as a desire to find more tolerable and/or convenient methods of treatment, have driven the search for other potential targeted therapies. In EG, there are increased levels of gastric inflammatory infiltrates, including T cells, eosinophils, and mast cells, and increased levels of chemokines and cytokines, including CCL26 (eotaxin-3), interleukin (IL)-4, IL-5, and IL-13. IL-5 is a direct eosinophil growth and activating factor, whereas IL-4 and IL-13 mediate several cardinal aspects of allergic inflammation including immunoglobulin E (IgE) production, T cell polarization to type 2 helper (Th2) cells, chemokine induction and subsequent leukocyte infiltration and activation, mucus production, barrier impairment, and end-organ dysfunction. IL-4 and IL-13 signal through a common receptor subunit, designated the IL-4Ra, that is required for signal transduction. Dupilumab is a fully human monoclonal antibody, directed against IL- 4Ra, that inhibits signaling of IL-4 and IL-13. Dupilumab has demonstrated efficacy and a favorable safety profile in adult patients with moderate-to-severe atopic dermatitis or asthma and has been recently approved for atopic dermatitis by the FDA and European Medicine Agency. The central hypothesis of this study is that dupilumab is safe and efficacious for reducing eosinophilia and a Th2 gene profile in EG. To this end, the Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR) will conduct a proof-of-principle, randomized, placebo-controlled trial in adults with EG. In Aim 1, we will test the primary hypothesis that dupilumab will decrease gastric eosinophil levels in patients with EG compared with placebo-treated patients. In Aim 2, we will test the hypothesis that dupilumab will reverse IL-13 signature genes expressed in the gastric mucosa of EG patients, including CDH26 and CCL26 and genes of type 2 cytokines (IL4, IL5, and IL13). It is anticipated that this study will provide proof-of-concept that EG is a type 2 allergic, immune-mediated disease and set the stage for the further development and eventual approval of a therapy for EG.