Budesonide versus fluticasone for treatment of eosinophilic esophagitis

描述(申请人提供)：布地奈德与氟替卡松治疗嗜酸性食管炎摘要嗜酸性食管炎(EoE)是一种新出现的免疫介导性疾病，其特征是嗜酸性粒细胞异常渗入食道粘膜，导致吞咽困难、进行性食道狭窄和食物嵌塞。虽然最初被认为是罕见的，但发病率和患病率正在急剧上升，在过去的十年里，EoE迅速成为上消化道疾病的主要原因。然而，EoE的治疗仍处于初级阶段，需要数据来指导实践。皮质类固醇是目前治疗EoE的主要药物，但目前还没有FDA批准的治疗EoE的药物。相反，哮喘制剂被使用，最常见的是多剂量吸入器(MDI)或布地奈德水溶液中的氟替卡松。这些药物是吞咽的，而不是吸入的，以覆盖食道，但尚不清楚氟替卡松或布地奈德是最有效的一线药物。对这些药物的反应有多持久，以及组织生物标记物的基线测量是否可以预测治疗反应，也是未知的。这些都是EoE中的关键问题和悬而未决的问题。我们最近进行了第一次也是唯一一次随机试验，直接比较了治疗EoE的两种外用制剂，发现吞咽粘性布地奈德浆液比雾化然后吞咽布地奈德水溶液更有效。然而，粘性布地奈德从未被直接与氟替卡松进行比较，这两种药物是治疗EoE的最常用药物。我们也有初步数据显示，主要碱性蛋白、嗜酸性粒细胞趋化蛋白-3和肥大细胞类胰蛋白酶的水平通过免疫组织化学染色食道活检来预测治疗反应。该项目的具体目标是：1)确定粘性布地奈德在改善EoE患者初始治疗疗程后的食道嗜酸性粒细胞计数和吞咽困难症状方面是否比氟替卡松MDI更有效；2)确定粘性布地奈德治疗EoE患者的症状和组织学复发是否比氟替卡松MDI少；3)确定主要碱性蛋白、嗜酸性粒细胞趋化因子-3和肥大细胞类胰酶的基线染色增加是否与局部应用皮质类固醇治疗的EOE患者的组织学反应有关。为了实现这些目标，我们将进行一项随机、双盲、临床试验，比较粘性布地奈德和氟替卡松MDI。这项创新和假设驱动的研究得到了PI产生的强大初步数据的支持，当时他得到了NIH职业发展奖的支持。它将由一个成熟而独特的多学科团队进行，该团队在EoE、临床试验、流行病学、病理学和翻译科学方面拥有国家公认的专业知识。这一结果将对治疗算法产生重大的临床影响 通过确定医生应该首先使用哪些药物并允许他们预测治疗反应来实现EoE。这项研究的数据也将很容易导致未来针对EoE患者的个体化治疗方案的试验。

DESCRIPTION (provided by applicant): Budesonide versus fluticasone for treatment of eosinophilic esophagitis ABSTRACT Eosinophilic esophagitis (EoE) is an emerging immune-mediated disease defined by abnormal infiltration of eosinophils into the esophageal mucosa, leading to dysphagia, progressive esophageal stenosis, and food impaction. Though initially thought to be rare, the incidence and prevalence are rising dramatically, and over the past decade EoE has rapidly become a major cause of upper gastrointestinal morbidity. The treatment of EoE, however, remains rudimentary and data are needed to inform practice. Corticosteroids are currently the mainstay of therapy for EoE, but there are no FDA-approved medications for EoE. Instead, asthma preparations are used, most commonly fluticasone in a multi-dose inhaler (MDI) or aqueous budesonide. These medications are swallowed, rather than inhaled, to coat the esophagus, but it is unknown whether fluticasone or budesonide is the most effective first line agent. It is also unknown how durable the response to these medications are, and whether baseline measurement of tissue biomarkers can predict treatment response. These are crucial and unanswered questions in EoE. We have recently conducted the first and only randomized trial directly comparing two topical formulations for treatment of EoE, and found that swallowing viscous slurry of budesonide was more effective than nebulizing and then swallowing an aqueous budesonide solution. However, viscous budesonide has never been directly compared with fluticasone, and these two medications are most commonly prescribed for EoE. We also have preliminary data showing that levels of major basic protein, eotaxin-3, and mast cell tryptase determined by immunohistochemical staining of esophageal biopsies predict treatment response. The specific aims of this project are 1) to determine whether viscous budesonide is more effective than fluticasone MDI for improving esophageal eosinophil counts and symptoms of dysphagia in patients with EoE after an initial treatment course; 2) to determine whether treatment with viscous budesonide results in less symptomatic and histologic recurrence than fluticasone MDI one year after the initial treatment course; and 3) to determine whether increased baseline staining of esophageal biopsies for major basic protein, eotaxin-3, and mast cell tryptase is associated with histologic response in EoE patients treated with topical corticosteroids. To achieve these aims, we will conduct a randomized, double-blind, clinical trial comparing viscous budesonide to fluticasone MDI. This innovative and hypothesis-driven study is backed by strong preliminary data generated by the PI while he was supported by an NIH career development award. It will be conducted by an established and unique multidisciplinary team with nationally recognized expertise in EoE, clinical trials, epidemiology, pathology, and translational science. The results will have a major clinical impact on the treatment algorithm for EoE by determining which medications doctors should use first and allowing them to predict treatment response. Data from this study will also readily lead to future trials of individualized treatment protocols for patients with EoE.