Effect of Varying Doses of Epicutaneous Immunotherapy vs Placebo on Reaction to Peanut Protein Exposure Among Patients With Peanut Sensitivity: A Randomized Clinical Trial

Abstract

Importance: Epicutaneous immunotherapy may have potential for treating peanut allergy but has been assessed only in preclinical and early human trials.

Objective: To determine the optimal dose, adverse events (AEs), and efficacy of a peanut patch for peanut allergy treatment.

Design, setting, and participants: Phase 2b double-blind, placebo-controlled, dose-ranging trial of a peanut patch in peanut-allergic patients (6-55 years) from 22 centers, with a 2-year, open-label extension (July 31, 2012-July 31, 2014; extension completed September 29, 2016). Patients (n = 221) had peanut sensitivity and positive double-blind, placebo-controlled food challenges to an eliciting dose of 300 mg or less of peanut protein.

Interventions: Randomly assigned patients (1:1:1:1) received an epicutaneous peanut patch containing 50 μg (n = 53), 100 μg (n = 56), or 250 μg (n = 56) of peanut protein or a placebo patch (n = 56). Following daily patch application for 12 months, patients underwent a double-blind, placebo-controlled food challenge to establish changes in eliciting dose.

Main outcomes and measures: The primary efficacy end point was percentage of treatment responders (eliciting dose: ≥10-times increase and/or reaching ≥1000 mg of peanut protein) in each group vs placebo patch after 12 months. Secondary end points included percentage of responders by age strata and treatment-emergent adverse events (TEAEs).

Results: Of 221 patients randomized (median age, 11 years [quartile 1, quartile 3: 8, 16]; 37.6% female), 93.7% completed the trial. A significant absolute difference in response rates was observed at month 12 between the 250-μg (n = 28; 50.0%) and placebo (n = 14; 25.0%) patches (difference, 25.0%; 95% CI, 7.7%-42.3%; P = .01). No significant difference was seen between the placebo patch vs the 100-μg patch. Because of statistical testing hierarchical rules, the 50-μg patch was not compared with placebo. Interaction by age group was only significant for the 250-μg patch (P = .04). In the 6- to 11-year stratum, the response rate difference between the 250-μg (n = 15; 53.6%) and placebo (n = 6; 19.4%) patches was 34.2% (95% CI, 11.1%-57.3%; P = .008); adolescents/adults showed no difference between the 250-μg (n = 13; 46.4%) and placebo (n = 8; 32.0%) patches: 14.4% (95% CI, -11.6% to 40.4%; P = .40). No dose-related serious AEs were observed. The percentage of patients with 1 or more TEAEs (largely local skin reactions) was similar across all groups in year 1: 50-μg patch = 100%, 100-μg patch = 98.2%, 250-μg patch = 100%, and placebo patch = 92.9%. The overall median adherence was 97.6% after 1 year; the dropout rate for treatment-related AEs was 0.9%.

Conclusions and relevance: In this dose-ranging trial of peanut-allergic patients, the 250-μg peanut patch resulted in significant treatment response vs placebo patch following 12 months of therapy. These findings warrant a phase 3 trial.

Trial registration: clinicaltrials.gov Identifier: NCT01675882.

Conflict of interest statement

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Sampson reports being a part-time employee of DBV Technologies; receiving consultant fees from Allertein Therapeutics, UCB, and Hycor and personal fees from UpToDate; holding stock options in DBV Technologies and Allertein Therapeutics; receiving grants from the National Institutes of Health, National Institute of Allergy and Infectious Diseases, and Food Allergy Research & Education; and co-owning a patent on FAHF-2. Dr Yang reported receiving research support from DBV Technologies during the conduct of the study. Dr Sussman reported receiving research support and consulting fees from DBV Technologies during the conduct of the study, as well as grants, consulting fees, and research support from Novartis; grants, consulting fees, and speaker fees from Aralez; consulting fees and research support from Merck, BioCryst, CSL Behring, and Dyax; grants and research support from Genentech; consulting fees from Pfizer; research support from GlaxoSmithKline, Stallergenes, GreenCross, and Kendrion; and grants from Aimmune Therapeutics outside the submitted work. Dr Brown-Whitehorn reported receiving consulting fees from DBV Technologies outside the submitted work. Dr Leonard reported that her institution received research support during the conduct of the study from DBV Technologies; she received support as a board member and a research grant from Food Allergy Research and Education (FARE); and her institution received research support from Aimmune Therapeutics and DBV Technologies. Dr Pongracic received nonfinancial and other support from DBV Technologies during the conduct of the study, as well as other support related to investigator meetings from Aimmune Therapeutics and nonfinancial support from Genentech/Novartis outside the submitted work; and her institution received research funding from Aimmune Therapeutics. Dr Assa’ad reported that her institution received research support and nonfinancial support from DBV Technologies during the conduct of the study, as well as research and nonfinancial support from Aimmune and Astellas outside the submitted work. Dr de Blay reported receiving grants and/or personal fees from Stallergenes Greer, Chiesi, ALK, Mundipharma, and Novartis, as well as serving as a board member for Stallergenes Greer, Novartis, ALK, Mundipharma, Meda Pharma, Boehringer, and AstraZeneca. Dr Bird reported receiving support for travel to meetings for the study or other purposes and his institution received research support during the conduct of the study from DBV Technologies; he received support as a board member at FARE, consultant fees from Aimmune Therapeutics and Wedbush Consulting, and speaking fees from Aimmune Therapeutics and DBV Technologies; and his institution received research support from Aimmune Therapeutics, DBV Technologies, the Foundation of the American College of Allergy, Asthma, and Immunology, and Nestle Health Sciences unrelated to the study. Dr Tilles reported receiving grants and/or personal fees from DBV Technologies, Aimmune, Astellas, Sanofi, Genentech, Immune Intolerance Network, Stanford University, Amgen, Circassia, Gilead, GlaxoSmithKline, Merck, Novartis, Pulmagen Therapeutics, Teva, Mylan, AstraZeneca, and FARE outside the submitted work. Dr Bourrier reported receiving personal fees from DBV Technologies during the conduct of the study, as well as nonfinancial support and/or personal fees from Stallergenes, Nestle, ALK, Mead Johnson, Novalac, and Thermo Fisher Scientific outside the submitted work. Dr Hébert reports receiving research support from DBV Technologies during the conduct of the study, as well as personal fees from GlaxoSmithKline, Merck, Novartis, Teva Pharmaceuticals, Shire, and CSL Behring outside the submitted work. Dr Green reported receiving research support from DBV Technologies during the conduct of the study, as well as research support and consultant fees from Aimmune Therapeutics and grants from FARE outside the submitted work. Dr Gerth van Wijk reported receiving grants from DBV Technologies during the conduct of the study, as well as personal fees from ALK-Abelló, Allergopharma, and Novartis and grants from Biomay, STW, and the Netherlands Lung Foundation outside the submitted work. Dr Knulst reported receiving research support from DBV Technologies during the conduct of the study. Dr Kanny reported receiving research support from DBV Technologies during the conduct of the study. Dr Schneider reported receiving research support from DBV Technologies during the conduct of the study and serving on the Medical Advisory Board for FARE. Dr Dupont is cofounder of DBV Technologies, holds stock in DBV, and has received an honorarium for chairing DBV Technologies’ Scientific Advisory Board. Dr Dupont also has patents related to a patch for screening the sensitivity state of patients with respect to an allergen and use thereof, immunotherapeutic method for increasing groundnut tolerance in a patient, and epicutaneous immunorebalancing. No other disclosures were reported.

Figures

Figure 1.. Patient Disposition Throughout the Phase 2b Trial and the Open-Label Extension Trial

DBCFC indicates double-blind, placebo-controlled food challenge; FEV, forced expiratory volume; PEF, peak expiratory flow; SPT, skin prick test. aMore than 1 criterion could apply to each patient. bPatients without an assessable DBCFC were considered nonresponders. cOne patient in the 100-μg patch group and 1 patient in the 250-μg patch group completed the DBCFC to peanut at month 12 but did not perform the end-of-study visit at month 12; these patients were considered as not having completed month 12. dSee Two-Year, Open-Label Extension Trial in the Results section for a description of the patient population in the open-label extension study. eSeven patients completed the DBCFC to peanut at month 36 but did not perform the end-of-study visit and were considered as not having completed month 36.

Figure 2.. Immunological Correlates Over Time in the Phase 2b Trial by Treatment Group and Age Groups

Peanut-specific IgE median change from baseline values and peanut-specific IgG4 median change from baseline values by treatment group and age groups. The error bars in all panels represent quartile 1 and quartile 3.

Figure 3.. Local Skin Reactions (Patient Diary Card) Over the First 3 Months of the Phase 2b Trial by Treatment Group

One patient in the placebo group did not maintain the diary card. Patients graded skin reactions (itching, redness, and swelling) daily on a scale from 0 to 3. Details are provided in the eAppendix in Supplement 2.