Efficacy and safety of oral immunotherapy in children aged 1-3 years with peanut allergy (the Immune Tolerance Network IMPACT trial): a randomised placebo-controlled study

Abstract

Background: For young children with peanut allergy, dietary avoidance is the current standard of care. We aimed to assess whether peanut oral immunotherapy can induce desensitisation (an increased allergic reaction threshold while on therapy) or remission (a state of non-responsiveness after discontinuation of immunotherapy) in this population.

Methods: We did a randomised, double-blind, placebo-controlled study in five US academic medical centres. Eligible participants were children aged 12 to younger than 48 months who were reactive to 500 mg or less of peanut protein during a double-blind, placebo-controlled food challenge (DBPCFC). Participants were randomly assigned by use of a computer, in a 2:1 allocation ratio, to receive peanut oral immunotherapy or placebo for 134 weeks (2000 mg peanut protein per day) followed by 26 weeks of avoidance, with participants and study staff and investigators masked to group treatment assignment. The primary outcome was desensitisation at the end of treatment (week 134), and remission after avoidance (week 160), as the key secondary outcome, were assessed by DBPCFC to 5000 mg in the intention-to-treat population. Safety and immunological parameters were assessed in the same population. This trial is registered on ClinicalTrials.gov, NCT03345160.

Findings: Between Aug 13, 2013, and Oct 1, 2015, 146 children, with a median age of 39·3 months (IQR 30·8-44·7), were randomly assigned to receive peanut oral immunotherapy (96 participants) or placebo (50 participants). At week 134, 68 (71%, 95% CI 61-80) of 96 participants who received peanut oral immunotherapy compared with one (2%, 0·05-11) of 50 who received placebo met the primary outcome of desensitisation (risk difference [RD] 69%, 95% CI 59-79; p<0·0001). The median cumulative tolerated dose during the week 134 DBPCFC was 5005 mg (IQR 3755-5005) for peanut oral immunotherapy versus 5 mg (0-105) for placebo (p<0·0001). After avoidance, 20 (21%, 95% CI 13-30) of 96 participants receiving peanut oral immunotherapy compared with one (2%, 0·05-11) of 50 receiving placebo met remission criteria (RD 19%, 95% CI 10-28; p=0·0021). The median cumulative tolerated dose during the week 160 DBPCFC was 755 mg (IQR 0-2755) for peanut oral immunotherapy and 0 mg (0-55) for placebo (p<0·0001). A significant proportion of participants receiving peanut oral immunotherapy who passed the 5000 mg DBPCFC at week 134 could no longer tolerate 5000 mg at week 160 (p<0·001). The participant receiving placebo who was desensitised at week 134 also achieved remission at week 160. Compared with placebo, peanut oral immunotherapy decreased peanut-specific and Ara h2-specific IgE, skin prick test, and basophil activation, and increased peanut-specific and Ara h2-specific IgG4 at weeks 134 and 160. By use of multivariable regression analysis of participants receiving peanut oral immunotherapy, younger age and lower baseline peanut-specific IgE was predictive of remission. Most participants (98% with peanut oral immunotherapy vs 80% with placebo) had at least one oral immunotherapy dosing reaction, predominantly mild to moderate and occurring more frequently in participants receiving peanut oral immunotherapy. 35 oral immunotherapy dosing events with moderate symptoms were treated with epinephrine in 21 participants receiving peanut oral immunotherapy.

Interpretation: In children with a peanut allergy, initiation of peanut oral immunotherapy before age 4 years was associated with an increase in both desensitisation and remission. Development of remission correlated with immunological biomarkers. The outcomes suggest a window of opportunity at a young age for intervention to induce remission of peanut allergy.

Funding: National Institute of Allergy and Infectious Disease, Immune Tolerance Network.

Conflict of interest statement

Declaration of interests SMJ reports grants from NIH-NIAID, Food Allergy Research & Education (FARE), Aimmune Therapeutic, DBV Technologies, Astellas, Sanofi, Regeneron, and Genentech; and personal fees from FARE, EMMES Corporation, and Aimmune Therapeutics. EHK reports personal fees from DBV Technologies, Aimmune Therapeutics, AllerGenis, Ukko, Vibrant America, Allakos, Kenota Health, and Duke Clinical Research Institute; and grants from FARE and the Wallace Research Foundation. KCN reports grants from NIAID, National Heart, Lung, and Blood Institute, National Institute of Environmental Health Sciences, and FARE; other fees from World Allergy Organization and Cour Pharma; other support from Before Brands, Alladapt, Latitude, IgGenix, Immune Tolerance Network (ITN), and NIH clinical research centres; and pending patent applications for inhibition of allergic reaction to peanut allergen using an IL-33 inhibitor (62/647,389), special oral formula for decreasing food allergy risk and treatment for food allergy (62/119,014), basophil activation based diagnostic allergy test (S10-392), granulocyte-based methods for detecting and monitoring immune system disorders (12/686,121), methods and assays for detecting and quantifying pure subpopulations of white blood cells in immune system disorders (12/610,940), mixed allergen compositions and methods for using the same (10/064,936), and microfluidic device and diagnostic methods for allergy testing based on detection of basophil activation (62/767,444). AN-W reports grants from NIH-NIAID, DBV Technologies, Astellas Pharma, and FARE; and grants and personal fees from Nestlé and Nutricia. RAW reports grants from NIAID, Aimmune, Astellas, DBV Technologies, Genentech, Regeneron, and Sanofi; and personal fees from UpToDate. HAS receives funding to his institution for grants from NIH-NIAID; consulting fees from DBV Technologies, N-Fold Therapeutics, and Siolta; and stock options from DBV Technologies and N-Fold Therapeutics. AMS reports grants from NIAID-ITN, FARE, Aimmune, DBV Technologies, Astellas, Sanofi, Regeneron, and Genentech; and personal fees from DBV Technologies. JW reports grants from NIAID and personal fees from DBV Technologies, ALK Abello, Genentech, and UpToDate. SBS reports grants from NIAID, Regeneron, DBV Technologies, Aimmune, Novartis, and Sanofi; and personal fees from AstraZeneca. MK reports grants from NIH and Department of Defence. JJ reports grants from NIAID. KS reports grants from NIH-NIAID. DCB reports grants from NIH-NIAID. HC reports grants from NIH-NIAID. DL reports grants from NIH-NIAID. All other authors declare no competing interests.

Copyright © 2022 Elsevier Ltd. All rights reserved.

Figures

Figure 1.. Trial Profile.

Participants were screened and randomized (2:1) to receive PnOIT or placebo in a blinded study protocol through week 160 and database lock. Following the study entry DBPCFC to 500 mg peanut protein, participants consumed daily, blinded OIT through week 134 per protocol then were assessed for protocol-defined clinical outcomes by DBPCFC to 5000 mg peanut protein at week 134 (desensitization) and after peanut avoidance for 26 weeks at week 160 (remission).

Figure 2.. Primary and Secondary Outcomes.

(A) Data are shown for primary (desensitization, in left panels) and secondary (remission, in right panels) endpoints measured by DBPCFC at weeks 134 and 160, respectively, for the ITT sample (upper panels) and PP sample (lower panels) comparing PnOIT (purple) and placebo (orange) arms. (B) Data are shown for the PnOIT arm. Baseline peanut-specific IgE (kUAL) is plotted on the y axis and age at screening (months) on the x axis; AUC=0.8072. Participants not achieving remission at the week 160 DBPCFC are shown in red, while those achieving remission at the week 160 DBPCFC are shown in blue. (C) A contour plot of predicted probability of remission from the logistic regression model plotted against baseline peanut-specific IgE (kUA/L) on the y axis and age at screening (months) on the x axis. Values in blue show >50% probability of remission, while values in red show <50% probability of remission.

Figure 2.. Primary and Secondary Outcomes.

(A) Data are shown for primary (desensitization, in left panels) and secondary (remission, in right panels) endpoints measured by DBPCFC at weeks 134 and 160, respectively, for the ITT sample (upper panels) and PP sample (lower panels) comparing PnOIT (purple) and placebo (orange) arms. (B) Data are shown for the PnOIT arm. Baseline peanut-specific IgE (kUAL) is plotted on the y axis and age at screening (months) on the x axis; AUC=0.8072. Participants not achieving remission at the week 160 DBPCFC are shown in red, while those achieving remission at the week 160 DBPCFC are shown in blue. (C) A contour plot of predicted probability of remission from the logistic regression model plotted against baseline peanut-specific IgE (kUA/L) on the y axis and age at screening (months) on the x axis. Values in blue show >50% probability of remission, while values in red show <50% probability of remission.

Figure 3.. Immunologic Changes over the Course of the Study.

Data are shown for the sample of PP participants that were evaluable while on treatment, during the avoidance phase and by DBPCFC after avoidance. Data are shown for time points including before treatment, week 30, week 82 or 95, week 134, and week 160 of the study. PnOIT participants were categorized as “desensitized, remission” (blue squares), “desensitized, no remission” (red diamonds), “not desensitized and no remission” (black asterisks) based on the results of the week 134 and week 160 DBPCFC. Panels A through C show levels of peanut-specific IgE (A), peanut-specific IgG4 to IgE ratios (B), and IgE to peanut component-specific Ara h2 (C) for the PnOIT outcome groups and placebo participants (orange triangles). (n=23 placebo, n=10 not desensitized, no remission, n=40 desensitized, no remission (panel C, n=39), and n=19 desensitized, remission, (panel C, n=18). Data are shown as means with 95% confidence intervals. +p≤0.05, ++p≤0.01 change from pretreatment in placebo participants. #p