The COMBINE Study is a 44-week, phase 2, multi-center, double-blinded, randomized, placebo-controlled trial of omalizumab and/or dupilumab with mOIT for the treatment of IgE-mediated multi-FA in participants aged 4–55 years. The study consists of a screening phase, followed by 44 weeks of active study participation with four distinct phases: run-in blockade of IgE with omalizumab, OIT dose escalation with/without blockade of IL-4/IL-13 signaling with dupilumab, maintenance dosing, and withdrawal (Figure 1). The study population is 110 participants with DBPCFC-confirmed allergies to peanut and to 2 or 3 additional protocol-specified foods, which were chosen for their relatively high prevalence (12, 15): almond, cashew, egg, fish, hazelnut, milk, sesame seed, shellfish, soy, walnut, and wheat. Inclusion and exclusion criteria are detailed in Table 1, and study-stopping rules are described in Supplementary Table S2.

Participants will be recruited across three study centers in California, United States: Stanford University, Palo Alto; the University of California Los Angeles, Los Angeles; and the University of California San Diego, La Jolla. Study objectives and endpoints are fully detailed in Table 2, with planned mechanistic assays described in Table 3 (additional details in the Supplementary Methods). A full schedule of study events, visits, and procedures is provided in detail in Table 4.

Participants meeting all eligibility criteria will proceed to Week 0 and undergo randomization in a 5:5:1 ratio to one of three cohorts using block randomization, stratified by number of allergens included in their mOIT treatment. The COMBINE trial is fundamentally a two-arm superiority study designed to test whether adding dupilumab to omalizumab-facilitated mOIT improves outcomes relative to omalizumab-facilitated mOIT alone. All primary and secondary analyses compare Cohorts A and B only: 1.

Cohort A (n = 50) will receive omalizumab for 8 weeks followed by 24 weeks of treatment with mOIT and placebo for dupilumab, then 12 weeks with no treatment.

Beginning at Week 0, participants will be dosed with omalizumab or placebo for omalizumab every 2 or 4 weeks according to their Week 0 body weight and most recent total IgE value. The weight- and IgE-based dosing algorithm targets 0.008 or 0.016 mg omalizumab/kg/(kUA/L) every 2 or 4 weeks, respectively, while not exceeding 20 mg/kg in a single administration, similar to the FDA-approved dosing tables for asthma (Supplementary Table S1). All doses of omalizumab/omalizumab placebo (as well as dupilumab/dupilumab placebo) will be dispensed to and administered by an unblinded injector in a fashion that maintains treatment blinding (i.e., shielded from the view of participants, visitors, and all other blinded individuals). All participants will be observed for 2 h after the first three omalizumab or placebo injections they receive in clinic and 30 min for injections thereafter from Week 0–8.

At Week 8, each participant will receive their final dose of omalizumab/placebo and, following observation, undergo an Initial Dose Escalation Day (IDED) for all foods to be included in their mOIT, starting at a dose of 1 mg protein per food (combined in a single mix) and escalating to 10 mg, 50 mg, 100 mg, 210 mg, 420 mg, and 1,000 mg protein per food sequentially as tolerated (Table 5). This IDED is designed to determine each participant's current tolerance and level in which they may begin mOIT dosing. If a participant does not tolerate at least 1 mg protein of each of their foods at IDED, they shall be deemed a treatment failure and will not receive further treatment nor undergo subsequent food challenges.

Following the Week 8 IDED, participants will begin daily mOIT dosing. Each participant will receive the highest tolerated dose at IDED as their home dose and return to the clinic every two weeks to attempt an observed dose escalation up to a maximum dose of 1,000 mg protein per allergen. The dose escalation schedule will follow that of the IDED (Table 5). Participants tolerating 1,000 mg protein of each food at the IDED will maintain that dose until Week 32. Dose escalation attempts will continue until Week 30 or until the participant reaches and tolerates 1,000 mg protein per allergen, whichever occurs first. Prior to each in-clinic dose escalation, participants shall be instructed to withhold their daily home mOIT dose and any prophylactic antihistamines. Throughout mOIT dosing, the participant's dose may be decreased as needed in select cases, such as intolerance or illness, and escalation attempts may be postponed for 1 or 2 visits based on clinical judgement; however, if a dose escalation attempt is not made within three consecutive scheduled clinic visits or the participant fails to successfully tolerate a dose escalation within three consecutive attempts, dosing will be discontinued and the participant shall be deemed a treatment failure. This rule will not apply in cases wherein the delay in escalation is due to administration of epinephrine or illness. Beginning at Week 10, participants will receive concomitant treatment with dupilumab or placebo dosed every 2–4 weeks according to FDA-approved dosing guidelines for atopic dermatitis, extended to those aged 4 years or older. The final dose of dupilumab or placebo will be administered at the Week 30 visit.

Upon reaching 1,000 mg protein per allergen, participants will maintain their mOIT dose with no further escalation. The maintenance phase for each participant begins when the participant reaches 1,000 mg protein per food and continues through the end of their Week 32 DBPCFCs. Each participant must escalate to and tolerate 1,000 mg protein per allergen on or before the end of their Week 30 visit; those unable to meet these criteria shall bedeemed a treatment failure and will not receive further study treatment nor undergo subsequent food challenges.

At Week 32, participants will undergo DBPCFCs to each allergen in their mOIT plus placebo on separate days while continuing daily mOIT dosing between challenge days. Each DBPCFC will consist of 8 doses given every 15–30 min in increasing amounts up to a cumulative total of 4,043 mg food protein or placebo as tolerated: 3 mg, 10 mg, 30 mg, 100 mg, 300 mg, 600 mg, 1,000 mg, and 2,000 mg protein. If the participant fails to tolerate at least 1,043 mg cumulative protein of at least one food allergen during the DBPCFCs, they shall be deemed a treatment failure and will not undergo subsequent food challenges. Participants tolerating at least one active food challenge at cumulative dose of at least 1,043 mg protein will continue into the withdrawal phase.

Following each participant's final Week 32 DBPCFC, those eligible to continue to the withdrawal phase will discontinue mOIT and dupilumab or placebo dosing through Week 44. This phase is designed to examine mechanisms underlying sustained unresponsiveness (SU). At Week 44, after 12 weeks off treatment, participants will undergo additional DBPCFCs to the specific foods to which they were desensitized (i.e., tolerated ≥1,043 mg cumulative protein) at Week 32 and placebo on separate days. The design and procedures for the Week 44 DBPCFCs are identical to those at Week 32. Each participant's sensitivity to food allergen will be defined as the dose at which the participant experiences dose-limiting allergic reactions as per the Consortium for Food Allergy Research Grading Scale for Systemic Allergic Reactions v.3.0 (22). Participants who pass one or more food challenges, defined as experiencing no or mild objective reactions to a cumulative dose of ≥1,043 mg protein per food allergen, at Week 44 will be considered to have achieved SU for the associated food allergen and completed the study. If the participant fails to pass the Week 44DBPCFC for all foods tested, they shall be deemed an SU failure.

The intent-to-treat (ITT) sample will include all participants who are enrolled. The safety sample is defined as all enrolled participants who receive at least one dose of mOIT. Participants in the safety sample will be analyzed according to the treatment that they actually received and will be utilized to assess differences in safety endpoints.

The primary analysis will be an ITT comparison of SU success rates between participants who received omalizumab plus mOIT with placebo for dupilumab (Figure 1, Cohort A) and participants who received omalizumab plus mOIT with dupilumab (Cohort B), where SU success is defined as the consumption of at least 1,043 mg cumulative protein at Week 44 DBPCFC with no or mild objective reactions (Table 2). A hierarchical endpoint analysis will be used, with peanut allergy as primary, to test the difference in proportions of participants who pass the peanut DBPCFCs between Cohorts A and B at Week 44. If this test is significant, the subsequent comparison will be a test between the proportions who pass peanut and at least one other food allergen. If this second test is significant, a third comparison will be made between Cohorts A and B of the proportion who pass all three DBPCFCs to active allergens. Missing tests or dropouts will be considered treatment failures and will be imputed as allergic cases. For all analyses, a two sided Fisher's exact test with an alpha level of 0.05 will be leveraged to test for significance. Based on results from the MTAX study (15), 26% of participants in Cohort A and 62% in Cohort B are expected to tolerate 1,043 mg of peanut protein at the Week 44 SU timepoint. Given this assumption, a cohort size of at least 43 participants per arm would provide a superior power of 93% at alpha level of 0.05 using the two-sided chi-square test. Considering a 15% dropout, 50 participants per arm is expected to result in sufficient power to detect the expected difference.

Supportive analyses of the primary endpoint will also be conducted, including a multivariable logistic regression for each of the three co-primary endpoint comparisons between Cohorts A and B. The model will be adjusted for important baseline demographic and clinical characteristics, such as age and number of original FAs that participants start with. If the first test uses exact logistic regression, the subsequent test will also be exact version. Further discussion of secondary, exploratory, mechanistic, descriptive analyses and power calculations may be found in the supplemental text.