Atsushi Fukunaga ^1* Yasumasa Kakei ² Sae Murakami ³ Yuji Kan ⁴ Koji Masuda ⁵ Masatoshi Jinnin ⁶ Ken Washio ⁷ Hiroo Amano ⁸ Tohru Nagano ⁹ Akihisa Yamamoto ¹⁰ Toshihiro Otsuka ¹ Shunsuke Takahagi ¹¹ Motoi Takenaka ¹² Naoko Ishiguro ¹³ Koremasa Hayama ¹⁴ Naoko Inomata ¹⁵ Yukinobu Nakagawa ¹⁶ Akiko Sugiyama ¹⁷ Michihiro Hide ¹¹

• ¹ Osaka Medical and Pharmaceutical University, Takatsuki, Osaka, Japan
• ² Kobe University Graduate School of Medicine, Kobe, Japan
• ³ Kobe University Hospital, Kobe, Hyōgo, Japan
• ⁴ Sapporo Medical University School of Medicine, Sapporo, Japan
• ⁵ Kyoto Prefectural University of Medicine Graduate School of Medical Science, Kyoto, Japan
• ⁶ Wakayama Medical University, Wakayama, Wakayama, Japan
• ⁷ Kobe City Nishi-Kobe Medical Center, Kobe City, Hyogo, Japan
• ⁸ School of Medicine, Iwate Medical University, Yahaba, Japan
• ⁹ Kobe City Medical Center General Hospital, Kobe, Hyōgo, Japan
• ¹⁰ Takarazuka City Hospital, Takarazuka, Hyōgo, Japan
• ¹¹ Hiroshima University, Hiroshima, Hiroshima, Japan
• ¹² Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Nagasaki, Japan
• ¹³ Tokyo Women's Medical University, Shinjuku, Tōkyō, Japan
• ¹⁴ Nihon University School of Medicine, Tokyo, Japan
• ¹⁵ Yokohama City University School of Medicine, Yokohama, Japan
• ¹⁶ Osaka University, Suita, Ōsaka, Japan
• ¹⁷ Fukuoka Hospital, National Hospital Organization (NHO), Fukuoka, Fukuoka, Japan

Background: For treating patients with refractory chronic spontaneous urticaria (CSU) resistant to standard doses of 2 nd generation H1-antihistamines (H1AH) the International and Japanese guidelines recommend increasing H1AH dose. The latter also recommends switching to a different H1AH. This study explored if the efficacy of the standard dose of bilastine 20 mg is non-inferior to that of doubledose of H1AH in patients with refractory CSU.Methods: This phase IV, multicenter, open-label, randomized, parallel-group trial evaluated the efficacy and safety of switching treatment to bilastine compared to treatment with a 2-fold dose of H1AH in patients with CSU refractory to standard dose H1AH. The primary endpoint was the mean total symptom score (TSS) at Day 5-7 after the start of administration.Results: Treatment efficacy and safety were evaluated in 128 patients (bilastine, n=64; 2-fold dose of H1AH, n=64). The mean TSS at Day 5-7 after the start of administration was smaller than the noninferiority margin of 0.8, demonstrating non-inferiority of the bilastine switching group to the double-dose H1AH group (0.17 (95% CI -0.32, 0.67)). No difference in Japanese version of Epworth Sleepiness Scale (JESS), DLQI, and urticaria activity score over 7 consecutive days (UAS7) was observed between the two groups. There were no serious adverse events in either group. H1AH-related adverse events occurred in 5 subjects (8 cases) and 2 subjects (3 cases) in the double-dose H1AH and bilastine groups, respectively.Switching treatment to bilastine demonstrated non-inferiority to a double-dose of H1AH in terms of efficacy in patients with CSU refractory to standard dose H1AH with a favorable safety profile.