A randomized, double blind, placebo controlled, phase 2 study testing the use of combination multi-allergen food desensitization with dupilumab or omalizumab in multi-food allergic individuals

一项随机、双盲、安慰剂对照 2 期研究，测试在多种食物过敏个体中使用多过敏原食物脱敏联合 dupilumab 或 omalizumab

• 批准号: 10553110
• 负责人: R. Sharon Chinthrajah
• 金额: $ 29.92万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10553110
• 关键词: randomized; double; blind; placebo; controlled

PROJECT SUMMARY It is estimated that as many as 30% of people with food allergy (FA) suffer from multiple FAs. The immune mechanisms underlying different clinical outcomes of oral immunotherapy (OIT) are not well understood, particularly in multi-food allergic individuals, and it is not clear to what extent combining OIT with other immunomodulating therapies might improve the safety or efficacy of OIT in FA, or the durability of favorable clinical outcomes. There is an unmet need for new therapies in FA, since OIT is associated with refractory or fail-to-treat populations, likely due to a number of cellular and molecular endotypes and clinical phenotypes. Because the cytokines IL-4 and IL-13 are important immune drivers of FA that act upstream of IgE in generating an allergic response, to address these challenges, our approach is to conduct a pilot, phase 2, multiple food allergen OIT (mOIT) study to compare the safety, efficacy and durability of mOIT combined with the anti-IL4Rα antibody dupilumab (DmO) vs. mOIT alone, and vs. mOIT combined with the anti-IgE antibody, omalizumab (OmO). We hypothesize that such combination therapy could improve the safety, efficacy and/or durability of mOIT in multi-FA patients. We also hypothesize that DmO, but not OmO, will improve sustained unresponsiveness outcomes vs. mOIT alone, due to the effects of dupilumab on the actions of IL-4 and IL-13. Our study will provide samples at screening, throughout OIT, and long-term after OIT, for key bioassays in Projects 2 (B cells), 3 (T cells) and 4 (basophils). Our study thus offers an arguably unique opportunity to achieve our overall objective: creating a comprehensive dataset of the clinical and immune monitoring outcomes of OIT protocols to better understand mechanisms of FA and to improve the safety and efficacy of FA therapy. Our specific aims are to: 1) Test whether treatment with mOIT combined with either omalizumab or dupilumab vs. mOIT alone results in a higher proportion of participants being able to pass a food challenge at week 24 (primary endpoint) and after a period of allergen withdrawal at week 30 (a secondary endpoint); 2) Determine whether these OIT protocols have lasting effects on the efficacy and safety of these treatments, and on changes in the subjects' immune responses that were induced by such treatments; and 3) Obtain GI biopsies of participants to permit a detailed analysis of immune cells and their products in GI tissues, at entry into the trial to identify features associated with FA at the disease site, and over the course of OIT to evaluate whether and how these features might change. Project 1 will be the first study to evaluate and compare each immunomodulating drug combined with mOIT vs. mOIT alone: the novelty of the study design combined with detailed mechanistic studies of blood and GI biopsies will permit us to advance the mechanistic understanding of FA and OIT, and to establish more effective and safer approaches to FA treatment.

项目总结 据估计，多达30%的食物过敏(FA)患者患有多种FA。免疫者 口服免疫疗法(OIT)不同临床结果背后的机制尚不清楚， 尤其是在对多种食物过敏的人中，目前尚不清楚OIT与其他 免疫调节治疗可能提高OIT在FA中的安全性或有效性，或改善有利的耐受性 临床结果。FA对新疗法的需求尚未得到满足，因为OIT与难治性或 治疗失败的人群，可能是由于一些细胞和分子内型和临床表型。 因为细胞因子IL-4和IL-13是FA的重要免疫驱动因子，作用于IgE的上游 过敏反应，为了应对这些挑战，我们的方法是进行试点，阶段2，多种食物 过敏原OIT(MOIT)研究：比较MOIT与抗IL4RIgE抗体联合应用的安全性、有效性和耐受性，以及MOIT与抗α抗体联合应用的安全性、有效性和持久性。 奥马珠单抗(Omo)。我们推测，这种联合治疗可以提高安全性、有效性和/或 MOIT在多发性FA患者中的耐受性。我们还假设DMO，而不是OMO，将持续改善 无反应性结果与仅MOIT相比，这是由于dupilumab对IL-4和IL-13活动的影响。 我们的研究将为OIT中的关键生物检测提供筛查、OIT全程和OIT后的长期样本。 项目2(B细胞)、3(T细胞)和4(嗜碱性粒细胞)。因此我们的研究提供了一个可以说是独一无二的机会 实现我们的总体目标：创建一个全面的临床和免疫监测数据集 OIT方案的结果，以更好地了解FA的机制，提高FA的安全性和有效性 FA疗法。我们的具体目标是：1)测试莫特与奥马珠单抗联合治疗 或者，单用dupiumab与moit相比，参与者能够通过食物挑战的比例更高 在第24周(主要终点)和在第30周停用变应原一段时间后(次要终点)； 2)确定这些OIT方案是否对这些治疗的有效性和安全性有持久影响； 以及由这种治疗引起的受试者免疫反应的变化；以及3)获得GI 参与者的活检，以便在进入时对胃肠道组织中的免疫细胞及其产物进行详细分析 进入试验，以确定与疾病部位FA相关的特征，并在OIT过程中进行评估 这些功能是否会发生变化以及如何变化。项目1将是第一个评估和比较它们的研究 免疫调节药物联合Moit与单用Moit：研究设计的新颖性与联合 血液和胃肠道活检的详细机制研究将使我们能够推进对机制的理解 对FA和OIT进行评估，并建立更有效和更安全的FA治疗方法。