Evaluation of oral immunotherapy efficacy and safety by maintenance dose dependency: A multicenter randomized study

Kiyotake Ogura; Noriyuki Yanagida; Sakura Sato; Takanori Imai; Komei Ito; Naoyuki Kando; Masanori Ikeda; Rumiko Shibata; Yoko Murakami; Takao Fujisawa; Mizuho Nagao; Norio Kawamoto; Naomi Kondo; Atsuo Urisu; Ikuya Tsuge; Yasuto Kondo; Kazuko Sugai; Osamu Uchida; Mitsuyoshi Urashima; Masami Taniguchi; Motohiro Ebisawa

doi:10.1016/j.waojou.2020.100463

Evaluation of oral immunotherapy efficacy and safety by maintenance dose dependency: A multicenter randomized study

World Allergy Organ J. 2020 Sep 29;13(10):100463. doi: 10.1016/j.waojou.2020.100463. eCollection 2020 Oct.

Authors

Kiyotake Ogura^{1

2}, Noriyuki Yanagida¹, Sakura Sato^{2

3}, Takanori Imai⁴, Komei Ito⁵, Naoyuki Kando⁵, Masanori Ikeda^{6

7}, Rumiko Shibata⁸, Yoko Murakami⁸, Takao Fujisawa⁹, Mizuho Nagao⁹, Norio Kawamoto¹⁰, Naomi Kondo¹⁰, Atsuo Urisu¹¹, Ikuya Tsuge¹¹, Yasuto Kondo¹¹, Kazuko Sugai¹², Osamu Uchida¹², Mitsuyoshi Urashima¹³, Masami Taniguchi^{2

3}, Motohiro Ebisawa^{2

3}

Affiliations

¹ Department of Pediatrics, National Hospital Organization, Sagamihara National Hospital, Kanagawa, Japan.
² Course of Allergy and Clinical Immunology, Juntendo University Graduate School of Medicine, Tokyo, Japan.
³ Department of Allergy, Clinical Research Center for Allergy and Rheumatology, National Hospital Organization, Sagamihara National Hospital, Kanagawa, Japan.
⁴ Department of Pediatrics, Showa University School of Medicine, Tokyo, Japan.
⁵ Department of Allergy, Aichi Children's Health and Medical Center, Aichi, Japan.
⁶ Department of Pediatrics, National Hospital Organization, Fukuyama Medical Center, Hiroshima, Japan.
⁷ Department of Pediatric Acute Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
⁸ Department of Pediatrics, National Hospital Organization, Fukuoka National Hospital, Fukuoka, Japan.
⁹ Institute for Clinical Research, National Hospital Organization, Mie National Hospital, Mie, Japan.
¹⁰ Department of Pediatrics, Graduate School of Medicine, Gifu University, Gifu, Japan.
¹¹ Department of Pediatrics, Fujita Health University, The Second Teaching Hospital, Aichi, Japan.
¹² Department of Pediatrics, National Hospital Organization, Yokohama Medical Center, Kanagawa, Japan.
¹³ Division of Molecular Epidemiology, The Jikei University School of Medicine, Tokyo, Japan.

Abstract

Background: Generally, oral immunotherapy (OIT) aims for daily administration. Recently, the efficacy of treatment with OIT at a low dose has been reported. However, the optimal dose and the evaluation of dose-dependent OIT outcome have not been described.

Methods: A multicenter, parallel, open-labeled, prospective, non-placebo controlled, randomized study enrolled 101 Japanese patients for treatment with OIT. We hypothesized that target dose OIT would induce short-term unresponsiveness (StU) earlier than reduced dose OIT. StU was defined as no response to 6200 mg whole egg, 3400 mg milk, and 2600 mg wheat protein, as evaluated by oral food challenge after 2-week ingestion cessation. To compare the two doses of OIT efficacy, the maximum ingestion doses during the maintenance phase of OIT were divided into 100%-dose or 25%-dose groups against their target StU dose, respectively. A total of 51 patients were assigned to the 100%-dose group [hen's egg (HE) = 26, cow's milk (CM) = 13, wheat = 12] and 50 to the 25%-dose group (HE = 25, CM = 13, wheat = 12). Primary outcome was established by comparing StU at 1 year. Secondary outcome was StU at 2 years and established by comparing allergic symptoms and immunological changes.

Results: The year 1 StU rates (%) for the 100%- and 25%-dose groups were 26.9 vs. 20.0 (HE), 7.7 vs. 15.4 (CM), and 50.0 vs. 16.7 (wheat), respectively. The year 2 StU rates were 30.8 vs. 36.0 (HE), 7.7 vs. 23.1 (CM), and 58.3 vs. 58.3 (wheat), respectively. There were no statistically significant differences in StU between years 1 and 2. The total allergic symptom rate in the 25%-dose group was lower than that in the 100%-dose group for egg, milk, and wheat. Antigen-specific IgE levels for egg-white, milk, and wheat decreased at 12 months.

Conclusions: Reduced maintenance dose of egg OIT showed similar therapeutic efficacy to the target dose. However, we were not able to clearly demonstrate the efficacy, particularly for milk and wheat. Reducing the maintenance dose for eggs, milk, and wheat may effectively lower the symptoms associated with their consumption compared to the target OIT dose. Furthermore, aggressive reduction of the maintenance dose might be important for milk and wheat, compared to the 25%-dose OIT.

Trial registration: UMIN000009373, Multicenter Oral Immunotherapy for Hen's Egg, Cow's Milk, and Wheat-Allergic Children at Outpatient Clinic.

Keywords: CM, cow’s milk; Desensitization; Dose-response relationship; EPIT, epicutaneous immunotherapy; FA, food allergy; Food hypersensitivity; HE, hens’ egg; Immunotherapy; OFC, oral food challenge; OIT, oral immunotherapy; SLIT, sublingual immunotherapy; SU, sustained unresponsiveness; StU, short-term unresponsiveness; sIgE, specific immunoglobulin E; sIgG, specific immunoglobulin G; sIgG4, specific immunoglobulin G4.