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粒细胞性食管炎的比较摘要嗜酸性粒细胞性食管炎（EoE）是一种新兴的免疫介导疾病，其定义为嗜酸性粒细胞异常浸润到食管粘膜中，导致吞咽困难、进行性食管狭窄和食物嵌塞。虽然最初被认为是罕见的，但其发病率和患病率正在急剧上升，在过去的十年中，EoE已迅速成为上消化道疾病的主要原因。然而，EoE的治疗仍然是初步的，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，但没有FDA批准的EoE药物。取而代之的是使用哮喘制剂，最常见的是多剂量吸入器（MDI）中的氟替卡松或布地奈德水溶液。这些药物被吞咽，而不是吸入，以覆盖食管，但目前还不清楚氟替卡松或布地奈德是最有效的一线药物。也不知道对这些药物的反应有多持久，以及组织生物标志物的基线测量是否可以预测治疗反应。这些都是EoE中至关重要且尚未回答的问题。我们最近进行了第一项也是唯一一项随机试验，直接比较了治疗Eoe的两种外用制剂，发现吞下粘稠的布地奈德浆比雾化然后吞下布地奈德水溶液更有效。然而，粘性布地奈德从来没有直接与氟替卡松比较，这两种药物是最常见的EoE处方。我们的初步数据还显示，通过食管活检免疫组织化学染色确定的主要碱性蛋白、嗜酸性粒细胞趋化因子-3和肥大细胞类胰蛋白酶水平可预测治疗反应。本项目的具体目的是：1）确定粘性布地奈德是否比氟替卡松MDI更有效地改善EoE患者在初始疗程后的食管嗜酸性粒细胞计数和吞咽困难症状; 2）确定粘性布地奈德治疗是否比氟替卡松MDI在初始疗程后一年的症状和组织学复发率更低;和3）确定食管活检中主要碱性蛋白、嗜酸性粒细胞趋化因子-3和肥大细胞类胰蛋白酶的基线染色增加是否与用局部皮质类固醇治疗的EoE患者的组织学应答相关。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生成的强有力的初步数据的支持，而他得到了NIH职业发展奖的支持。它将由一个建立和独特的多学科团队进行，该团队在EoE，临床试验，流行病学，病理学和转化科学方面具有国家认可的专业知识。结果将对治疗算法产生重大临床影响， EoE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。这项研究的数据也将很容易导致未来对EoE患者进行个性化治疗方案的试验。

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.