Anti-IgE treatment with oral immunotherapy in multifood allergic participants: a double-blind, randomised, controlled trial

Abstract

Background: Despite progress in single food oral immunotherapy, there is little evidence concerning the safety and efficacy of treating individuals with multiple food (multifood) allergies. We did a pilot study testing whether anti-IgE (omalizumab) combined with multifood oral immunotherapy benefited multifood allergic patients.

Methods: We did a blinded, phase 2 clinical trial at Stanford University. We enrolled participants, aged 4-15 years, with multifood allergies validated by double-blind, placebo-controlled food challenges to their offending foods. Inclusion criteria included a positive skin prick test of 6 mm or more (wheal diameter, above the negative control), a food-specific serum IgE concentration of more than 4 kU/L for each food, or both, and a positive double-blind, placebo-controlled food challenge at 500 mg or less of food protein. Exclusion criteria included eosinophilic oesophagitis and severe asthma. Participants were randomised (3:1) with a block size of four, to receive multifood oral immunotherapy to two to five foods, together with omalizumab (n=36) or placebo (n=12). 12 individuals who fulfilled the same inclusion and exclusion criteria were included as controls. These individuals were not randomised and received neither omalizumab nor oral immunotherapy. Omalizumab or placebo was administered subcutaneously for 16 weeks, with oral immunotherapy starting at week 8, and was stopped 20 weeks before the exit double-blind, placebo-controlled food challenge at week 36. The primary endpoint was the proportion of participants who passed double-blind, placebo-controlled food challenges to at least two of their offending foods. This completed trial is registered with ClinicalTrials.gov, number NCT02643862.

Findings: Between March 25, 2015, and Aug 18, 2016, 165 participants were assessed for eligibility, of whom 84 did not meet the inclusion criteria and 21 declined to participate. We enrolled and randomised 48 eligible participants and the remaining 12 patients were included as nonrandomised, untreated controls. At week 36, a significantly greater proportion of the omalizumab-treated (30 [83%] of 36) versus placebo (four [33%] of 12) participants passed double-blind, placebo-controlled food challenges to 2 g protein for two or more of their offending foods (odds ratio 10·0, 95% CI 1·8-58·3, p=0·0044). All participants completed the study. There were no serious or severe (grade 3 or worse) adverse events. Participants in the omalizumab group had a significantly lower median per-participant percentage of oral immunotherapy doses associated with any adverse events (27% vs 68%; p=0·0082). The most common adverse events in both groups were gastrointestinal events.

Interpretation: In multifood allergic patients, omalizumab improves the efficacy of multifood oral immunotherapy and enables safe and rapid desensitisation.

Funding: US National Institutes of Health (NIH).

Figure 1:

Consort Diagram demonstrating the phase 2 randomized placebo-controlled trial design (Omalizumab vs. Placebo arms).

Figure 2:. Overview of foods in each participant’s multifood OIT

Overview of foods in each participant’s multifood OIT (all shown foods had a positive DBPCFC at baseline for that participant), grouped by study arm (red for omalizumab arm, blue for placebo arm) and primary endpoint outcome. The outcome of the 2 g DBPCFC for each food in week 36 is shown in green when negative (i.e., the participant passed the DBPCFC for that food) and in dark red when positive (i.e., the participant failed the DBPCFC for that food). The failures didn’t undergo food challenges in week 36 and the foods in their multifood OIT are marked by gray boxes.

Figure 3:. Percentage of participants per study arm who tolerated 2 g (primary endpoint) or 4 g (secondary endpoint) in DBPCFCs to at least 2 foods at week 36.

Every participant who passed the primary endpoint also passed this secondary endpoint. Significantly more participants in the omalizumab arm (83%) passed either endpoint than in the placebo arm (33%) [P = 0·004, OR: 10, 95% CI: 1·8 – 58·3].

Figure 4:. Time since starting therapy (i.e., starting omalizumab or placebo) to reach a 2 g maintenance dose per food

(A) The time since starting therapy (i.e., starting omalizumab or placebo) for participants in each study arm to reach a 2 g maintenance dose per food. Study failures (6 in the omalizumab arm, 8 in the placebo arm) who never reached 2 g maintenance are censored (marked by vertical black tick marks) at week 36. Participants receiving omalizumab reached the 2 g maintenance dose per food faster (P = 0·001) than the participants on placebo. (B) The time since starting therapy for participants in the omalizumab arm to reach a 2 g maintenance dose per food, stratified by the number of foods in that participant’s multifood OIT. Study failures are censored (marked by vertical black tick marks) at week 36. Participants with lower numbers of foods in their OIT show a trend of reaching the 2 g maintenance dose per food faster (P = 0·03).

Figure 5:. Tolerated dose at IDED (initial dose escalation day).

(A) Each data point represents the tolerated dose per food (total tolerated dose divided by the number of foods in the multifood OIT) for each participant stratified by study arm (left) or by study arm and primary endpoint outcome (middle and right). (B) The total dose of food protein tolerated at IDED for each participant. The ‘hinges’ represent the first and third quartile. The whiskers are the smallest and largest values after outliers are excluded. Outliers are defined as values greater than the 75th percentile plus 1·5 times the interquartile range (IQR), or less than 25th percentile minus 1·5 times the IQR.