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

项目摘要 据估计，多达30%的食物过敏（FA）患者患有多种FA。免疫 口服免疫疗法（OIT）的不同临床结果的潜在机制尚未得到很好的理解， 特别是在多种食物过敏的个体中，目前尚不清楚OIT与其他药物的结合程度 免疫调节治疗可能会改善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。由于OIT与难治性或复发性疾病相关，因此FA的新疗法需求尚未得到满足。 治疗失败的人群，可能是由于许多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，其在产生FA的过程中作用于IgE的上游， 为了应对这些挑战，我们的方法是进行试点，第2阶段，多种食物 过敏原OIT（mOIT）研究，比较mOIT与抗IL联合治疗的安全性、有效性和持久性4 R α抗体dupilumab（Dm O）与mOIT单药治疗以及与mOIT联合抗IgE抗体治疗的比较， 奥马珠单抗（OmO）。我们假设这样的联合治疗可以改善安全性、有效性和/或 多FA患者中mOIT的持久性。我们还假设，DmO，而不是OmO，将改善持续的 与mOIT单药相比，无反应性结局，因为dupilumab对IL-4和IL-13的作用。 我们的研究将在筛选时、整个OIT期间和OIT后长期提供样本，用于关键的生物测定， 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：创建临床和免疫监测的综合数据集 OIT方案的结果，以更好地了解FA的机制，并提高安全性和有效性 FA疗法。我们的具体目标是：1）测试mOIT与奥马珠单抗联合治疗是否 或dupilumab与单独mOIT相比，导致更高比例的受试者能够通过食物挑战 第24周（主要终点）和第30周过敏原戒断期后（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具有持久影响， 以及由这种治疗诱导的受试者免疫应答的变化;以及3）获得GI 入组时，对参与者进行活检，以详细分析GI组织中的免疫细胞及其产物 进入试验，以确定疾病部位与FA相关的特征，并在OIT过程中评估 这些特征是否以及如何改变。项目1将是第一个评估和比较每一个项目的研究。 免疫调节药物联合mOIT与单独mOIT：研究设计的新奇， 对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 的FA和OIT，并建立更有效和更安全的方法来治疗FA。

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.