A Randomized Controlled Trial of Oral Immunotherapy Versus Allergen Avoidance in Children Under 2 Years With Food Allergy

Overview

The goal of this clinical trial is to learn whether oral immunotherapy (OIT) is safe and effective for treating food allergy in children aged 0-2 years with peanut, tree nut, or sesame allergy. The study also aims to identify biological mechanisms and biomarkers associated with natural tolerance development and successful OIT using a systems biology approach. The main questions it aims to answer are: 1. Does oral immunotherapy increase the likelihood of successful desensitization and sustained unresponsiveness compared with allergen avoidance? 2. Can immune, microbiome, metabolomic, genetic, and epigenetic profiles predict treatment response, natural tolerance development, and long-term outcomes? Researchers will compare children receiving oral immunotherapy with children receiving standard care (allergen avoidance) to determine differences in treatment success, sustained unresponsiveness, safety, quality of life, and biological markers. Participants will: * Be randomized to either oral immunotherapy or allergen avoidance for 18-24 months. * Undergo oral food challenges at study visits to assess allergic reactivity and treatment outcomes. * Provide blood, urine, hair, skin swabs, skin tape strips, throat swabs, nasal lining fluid, and stool samples at baseline and at the end of the study for immune, microbiome, metabolomic, gene expression, and epigenetic analyses. * Complete allergy assessments, including skin prick testing and clinical evaluations. * Have allergic symptoms, adverse reactions, and development of other allergic diseases monitored throughout the study. * Have parents complete questionnaires assessing food allergy-related quality of life, anxiety, and coping.

Food allergy affects approximately 4% of children worldwide and has increased over the past two decades, imposing substantial psychosocial and economic burden on affected families. For years, management relied on strict avoidance of the allergen and carrying an epinephrine autoinjector, which leads to tolerance development among 10-30% with peanut, tree-nut and sesame allergy. Treatments for food allergy such as biologics and oral immunotherapy (OIT) have shown a promising safety and efficacy profile in most studies, especially in younger children, but are not yet standard of care. Biologics, including monoclonal antibodies targeting IgE (such as omalizumab) or key type 2 inflammatory pathways (e.g. dupilumab), offer an emerging strategy for managing food allergy. Used as stand-alone therapy, biologics can raise the threshold for allergic reactions and reduce symptom severity. Moreover, biologics have also been studied as adjuncts to OIT, where they may improve safety profiles, reduce dosing-related reactions, and facilitate more rapid desensitization. However, trials in young children assessing both safety, efficacy, mechanism and potential biomarkers are needed to inform personalized strategies, determining which children might benefit most from an avoidance strategy, OIT alone, biologics alone, or a combined approach. Currently, Palforzia is the only European Medicines Agency (EMA) approved OIT product available and approved for children from 4-17 years of age, whereas there are no OIT treatment options for the youngest children, where the prevalence of food allergy is highest. Peanut OIT is gaining support based on real-world evidence, but OIT RCTs in young children under age 6 years are scarce and limited to studies of peanut and egg. The short term desensitization rates following peanut OIT range from 60% to 85%, and are higher when treatment begins in preschool age. Gastrointestinal and respiratory symptoms are common during peanut OIT, whereas rates of anaphylaxis requiring epinephrine are varying but relatively low, where up to 14% has been reported. Data for tree-nut OIT, e.g., hazelnut, cashew, pistachio, walnut and almond, is limited to a single-center retrospective study on hazelnut OIT in children \< 18 years, and a single-center prospective cohort study on walnut OIT in children from 4-20 years. Further, data on tree-nut allergy has been extrapolated from an omalizumab-supported multifood OIT study in children from 4-15 years, which included cashew, walnut, hazelnut, and almond. Although outcomes and study design varied considerably, short term desensitization following tree-nut OIT ranged from 34% to 100%. Analysis of preliminary safety data is promising, with primarily mild reactions comparable with peanut OIT. Evidence for sesame OIT is very limited and solely based on small observational cohorts, case series, or extrapolated from multifood OIT protocols including sesame. Reported short term desensitization rates vary from 55% to 80%, and the majority of adverse reactions are mild. Thus, while short term safety and efficacy of peanut, tree-nut, and sesame OIT seems promising, RCTs are needed in the youngest children, where food allergy is most prevalent. Moreover, although short term desensitization rates are encouraging, long term tolerance to the food - known as sustained unresponsiveness after discontinuing OIT - has proven more elusive. Follow-up studies show that many children relapse once therapy ends. Thus, there is a need for studies to identify underlying mechanisms and biomarkers predicting sustained unresponsiveness versus relapse, i.e. personalized treatment. In addition, some children will outgrow their food allergy during avoidance, i.e., natural tolerance development, but the mechanisms underlying natural tolerance are poorly understood, and no reliable predictors exist. Further, open-label quality-of-life (QoL) studies have consistently shown that OIT substantially reduces family anxiety concerning accidental exposures and improves daily functioning, but this still needs to be investigated in the youngest children in RCTs with a proper comparison of children undergoing avoidance vs. OIT. Finally, no previous study has investigated facilitators and barriers for implementing OIT in clinical practice, despite its higher resource demands and higher risk of adverse reactions compared to standard of care.