To the Editor: Chronic urticaria, prevalent globally and increasing in China, predominantly affects young and middle-aged women, impacting their quality of life (QoL).[1] Standard treatment involves second-generation H1 antihistamines, with bilastine showing promise due to its selective action and minimal side effects. However, direct comparative studies are scarce, particularly in the Chinese population. We aimed to evaluate the efficacy and safety of bilastine compared to levocetirizine in Chinese patients. This multicenter, double-blind, double-dummy, non-inferiority, phase III trial conducted at 18 centers (CTR20181967, www.chinadrugtrials.org.cn; ChiCTR2300072867, www.chictr.org.cn) was approved by the Medical Ethics Committee of Peking University People's Hospital (No. 2018PHA062-002) [Supplementary Table 1, https://links.lww.com/CM9/B953]. All patients provided written informed consent. Participants with chronic idiopathic urticaria who met the eligible criteria [Supplementary Table 2, https://links.lww.com/CM9/B953] were randomized to 1:1 to 28-day treatment with bilastine 20 mg or levocetirizine 5 mg daily, alongside matching placebos, using a centralized system to ensure blinding. The primary endpoint was the Total Symptom Score (TSS) for itching, wheals number, and size. Secondary endpoints encompassed detailed TSS analysis, Urticaria Composite Score (UCS), Dermatology Life Quality Index (DLQI), Visual Analog Scale (VAS), and Global Clinical Impression (GCI). Safety was continuously monitored through adverse events (AEs) follow-up. Assuming an 80% power, one-side alpha of 0.025, a standard deviation of 2.16, a non-inferior margin of 0.8, and a 20% dropout rate, it was planned to randomize 288 participants (bilastine:levocetirizine = 144:144). The primary endpoint analysis of non-inferiority was assessed on the Per-Protocol Population (PP) set and the secondary efficacy analyses were performed in the modified intent-to-treat (mITT) population. In this study, 288 patients were randomized across two groups (144 each) [Supplementary Figure 1, https://links.lww.com/CM9/B953]. In the mITT population, mean ages were 35.5 ± 10.8 years and 36.5 ± 12.1 years in the bilastine and levocetirizine groups, respectively, with male representation at 49.6% and 37.1%. Baseline characteristics showed no significant differences between groups [Supplementary Table 3, https://links.lww.com/CM9/B953]. In the primary endpoint analysis of the PP set (bilastine: 122, levocetirizine: 120), baseline TSS for reflective symptoms were 4.06 ± 2.04 (bilastine) and 4.43 ± 2.10 (levocetirizine). By day 28, these scores reduced to 1.53 ± 1.91 and 1.37 ± 1.88, respectively [Table 1]. The mean changes from baseline in TSS (reflective) were –2.54 ± 2.59 (bilastine) and –3.06 ± 2.47 (levocetirizine), with least squares (LS) mean difference of 0.17 (–0.19, 0.54), demonstrating non-inferiority [Supplementary Figure 2, https://links.lww.com/CM9/B953]. Superiority was not established in exploratory analysis. Daytime and nighttime scores for itching intensity, wheals number, and maximum wheal size decreased in both groups, with no significant differences in changes between groups (P >0.05 for all). The areas under the TSS score curves were 44.09 ± 43.35 (bilastine) and 41.44 ± 41.55 (levocetirizine), not significantly different (P = 0.604). Participant-assessed TSS (instantaneous) decreased from baseline to day 28 (bilastine: 3.19 ± 2.70 to 1.34 ± 1.87; levocetirizine: 3.20 ± 2.75 to 1.06 ± 1.77), with no significant intergroup differences in changes (–2.13 ± 2.94 vs. –2.04 ± 2.68, P = 0.829). Investigator-assessed TSS (instantaneous) also showed comparable decreases in both groups by day 28 (–2.12 ± 2.76 bilastine, –2.29 ± 2.93 levocetirizine; P = 0.861) [Table 1]. Table 1 - Efficacy endpoints of bilastine compared to levocetirizine in Chinese patients. Items Bilastine 20 mg Levocetirizine 5 mg Difference, LS means (95% CI) P-value Primary endpoint, n 122 120 TSS (reflective) Day 28 1.53 ± 1.91 1.37 ± 1.88 Change from baseline –2.54 ± 2.59 –3.06 ± 2.47 0.17 (–0.19, 0.54) 0.356* Secondary endpoint, n 139 140 TSS domain Itching intensity, daytime, LS mean (95% CI) –0.81 (–0.89, –0.73) –0.88 (–0.96, –0.79) 0.07 (–0.05, 0.18) 0.2525 Itching intensity, nighttime, LS mean (95% CI) –1.0 (–1.08, –0.92) –1.07 (–1.15, –0.99) 0.07 (–0.05, 0.18) 0.2393 Wheals number, daytime, LS mean (95% CI) –0.67 (–0.76, –0.58) –0.75 (–0.84, –0.66) 0.08 (–0.05, 0.21) 0.2033 Wheals number, nighttime, LS mean (95% CI) –0.83 (–0.92, –0.74) –0.87 (–0.96, –0.79) 0.05 (–0.08, 0.17) 0.4773 Maximum size of wheals, daytime, LS mean (95% CI) –0.84 (–0.94, –0.74) –0.88 (–0.98, –0.78) 0.04 (–0.11, 0.18) 0.6239 Maximum size of wheals, nighttime, LS mean (95% CI) –1.03 (–1.14, –0.92) –1.02 (–1.13, –0.91) –0.01 (–0.16, 0.14) 0.9039 UCS (reflective) Day 28 0.98 ± 1.22 0.87 ± 1.19 Change from baseline –1.62 ± 1.63 –2.05 ± 1.59 0.171 Participant-assessed TSS (instantaneous) Day 28 1.34 ± 1.87 1.06 ± 1.77 Change from baseline –2.13 ± 2.94 –2.04 ± 2.68 0.829 Investigator-assessed TSS (instantaneous) Day 28 1.35 ± 1.83 1.30 ± 2.09 Change from baseline –2.12 ± 2.76 –2.29 ± 2.93 0.861 Participant-assessed UCS (instantaneous) Day 28 0.9 ± 1.2 0.6 ± 1.1 Change from baseline –1.3 ± 1.9 –1.4 ± 1.7 0.127 Investigator-assessed USC (instantaneous) Day 28 0.9 ± 1.2 0.8 ± 1.2 Change from baseline –1.3 ± 1.8 –1.5 ± 1.8 0.522 Investigator's GCI, n (%) Marked improvement 71 (51.1) 71 (50.7) 0.420 Moderate marked improvement 41 (29.5) 48 (34.3) 0.964 Minimal slight improvement 20 (14.4) 13 (9.3) 0.805 No change or worse 1 4 Not evaluated 6 4 QoL Day 28, mean ± SD 4.1 ± 4.6 3.7 ± 4.3 Change from baseline, mean ± SD –6.1 ± 5.1 –7.2 ± 5.8 0.209 Sleep quality impacted by chronic idiopathic urticarial, n (%) 0.707 Not at all 80 (57.6) 89 (63.6) Somewhat 43 (30.9) 37 (26.4) Moderately 7 (5.0) 8 (5.7) A lot 2 (1.4) 1 (0.7) Very much 1 (0.7) 0 *Non-inferiority test. Data were shown as mean ± SD, except when indicated otherwise. CI: Confidence interval; GCI: Global clinical impression; LS: Least square; QoL: Quality of life; SD: Standard deviation; TSS: Total Symptom Score; UCS: Urticaria Composite Score. Regarding secondary endpoints, baseline UCS (reflective) scores were 2.59 ± 1.28 (bilastine) and 2.90 ± 1.37 (levocetirizine), decreasing to 0.98 ± 1.22 and 0.87 ± 1.19, respectively, on day 28. Changes in UCS (reflective) were not significantly different (–1.62 ± 1.63 vs. –2.05 ± 1.59, P = 0.171). Both participant-assessed and investigator-assessed UCS (instantaneous) scores decreased similarly by day 28, with no significant difference in changes (participant-assessed: –1.3 ± 1.9 vs. −1.4 ± 1.7, P = 0.127; investigator-assessed: –1.3 ± 1.8 vs. –1.5 ± 1.8, P = 0.522). The investigator's GCI showed similar proportions of marked improvements (51.1% vs. 50.7%, P = 0.420) and moderate to minimal improvements (P >0.05) between groups. The DLQI scores on day 28 were 4.1 ± 4.6 and 3.7 ± 4.3, indicating comparable QoL improvements (–6.1 ± 5.1 vs. –7.2 ± 5.8, P = 0.209). The mean VAS scores for discomfort decreased significantly in both groups (bilastine: 58.50 ± 22.13–20.53 ± 20.72; levocetirizine: 61.68 ± 23.21–16.55 ± 20.55), with no significant differences on days 14 and 28 (P >0.05). The proportions of patients unaffected in sleep by chronic idiopathic urticaria increased similarly post-treatment (P >0.05) [Table 1]. In this study, exposure duration averaged 26.7 ± 3.8 days (bilastine) and 26.1 ± 5.1 days (levocetirizine). Treatment-emergent AEs (TEAEs) were reported in 30.2% (bilastine) and 34.0% (levocetirizine) of participants, with no dose adjustments or treatment interruptions due to TEAEs. Treatment discontinuations due to TEAEs occurred in one bilastine participant (0.7%, anxiety) and two levocetirizine participants (1.4%, blurred vision; diarrhea and lethargy). Common TEAEs in ≥3% of either group included sinus arrhythmia, elevated blood triglycerides, electrocardiogram T wave abnormality, hyperuricemia, and somnolence [Supplementary Table 4, https://links.lww.com/CM9/B953]. No serious adverse events were reported, and all TEAEs were mild to moderate. Moderate TEAEs were observed in 3.6% of bilastine and 2.1% of levocetirizine participants. In this study, bilastine significantly alleviated symptoms of chronic idiopathic urticaria in Chinese patients. It also showed non-inferiority to levocetirizine, aligning with Western population studies[2] and meta-analyses.[3] Although superiority wasn't established, possibly due to primary endpoint selection and insufficient power for superiority analysis, bilastine stands as a strong first-line treatment candidate for Chinese patients with chronic idiopathic urticaria, despite potential regional variations in rescue medication use. Podder et al[4] reported notable improvements in QoL with both bilastine and levocetirizine, with bilastine showing fewer TEAEs of somnolence. This aligns with a meta-analysis underscoring bilastine's efficacy in symptom control and QoL enhancement.[5] Nevertheless, morning administration may lead to heightened somnolence in the levocetirizine group. This study demonstrated that bilastine significantly alleviated physical discomfort from chronic idiopathic urticaria, and might enhance participants' QoL and sleep. Bilastine's minimal sedation and negligible impact on tasks like driving may be due to its lower brain histamine H1 receptor occupancy,[6] suggesting it as a potentially preferred option for managing chronic idiopathic urticaria. This trial, while contributing valuable insights, has limitations. The 28-day treatment period does not fully represent the chronic nature of idiopathic urticaria where long-term treatment is common. The study also focused solely on the approved dose of bilastine, although higher dosing has been showed to be safe and effective. The use of different assessment tools also poses comparability challenges. Despite these constraints, bilastine demonstrated significant improvement in symptoms and QoL, with a safety profile comparable to levocetirizine, suggesting its efficacy for Chinese patients with chronic idiopathic urticaria. Further studies are needed to explore long-term treatment outcomes and dosing variations of bilastine. Acknowledgments This study was sponsored by Menarini China. The authors would like to thank Menarini for sponsoring this phase III study IQVIA for providing CRO services and MedSci for medical writing services. In addition, we would like to thank all the staff from 18 hospitals who participated in this study. Conflicts of interest None.
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