This was an analysis of the subgroup of Korean patients who participated in the SIROCCO trial. Full details of the SIROCCO trial have been published.15 SIROCCO was a randomized, double-blind, parallel-group, placebo-controlled Phase III trial of 1,204 patients enrolled in 17 contries, including South Korea. This study included patients aged 12-75 years with a history of physician-diagnosed asthma that required treatment with medium- to high-dosage ICS/LABA for at least 12 months before enrollment. Eligible patients had 2 or more asthma exacerbations in the 12 months before enrollment that required systemic corticosteroid treatment or a temporary increase in their usual maintenance OCS dosages. Patients also received treatment with high-dosage ICS/LABA (>500 µg/d fluticasone propionate dry powder formulation or equivalent total daily dosage) with or without OCS and additional asthma controllers for ≥3 months before enrollment. The study was conducted in accordance with the Declaration of Helsinki, International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use/Good Clinical Practice guidelines and the ethics committee at each participating site.

The SIROCCO trial consisted of an enrollment visit (week −4), screening phase (weeks −4 to 0), randomization (week 0), treatment period (weeks 0–48), and follow-up visit (week 56). Eligible patients were randomized 1:1:1 to receive benralizumab 30 mg by subcutaneous injection every 4 weeks (Q4W) or Q4W for the first three doses then every 8 weeks thereafter (Q8W; placebo was administered at the interim visits Q4W to maintain blinding) or placebo Q4W for 48 weeks (Fig. 1). Benralizumab and placebo were provided by AstraZeneca (Gaithersburg, MD, USA). Patients in the Q4W arm received their last dose of benralizumab at week 44, and patients in the Q8W arm received their last dose of benralizumab at week 40. Patients continued to receive their background asthma controller medications without dosage modification throughout the trial. Patients with blood eosinophil counts ≥ 300 cells/µL and < 300 cells/µL were recruited in a 2:1 ratio.

The primary efficacy endpoint was the annual rate of asthma exacerbations vs. placebo. An exacerbation was defined as worsening of asthma that led to: 1) the use of systemic corticosteroids (or a temporary increase in background OCS dosages) for ≥3 days or a single injection of corticosteroids, 2) an emergency department or urgent care visit for <24 hours because of asthma that required use of systemic corticosteroids, or 3) an inpatient hospitalization for ≥24 hours because of asthma. Worsening of asthma was defined as any new or increased asthma signs or symptoms that were concerning to the patient or related to an Asthma Daily Diary alert.

The key multiplicity-protected secondary endpoints in the main trial were prebronchodilator forced expiratory volume in 1 second (FEV1) and total asthma symptom score. The primary and key secondary endpoints included patients with blood eosinophil counts ≥ 300 cells/μL. Spirometry was conducted at the study centers. Patients recorded their asthma symptoms and results of peak expiratory flow measurements (taken using a handheld spirometric device) twice daily in the Asthma Daily Diary using an electronic patient-reported outcomes device. The Asthma Daily Diary was completed by patients in the morning upon waking and in the evening before going to bed. The morning and evening assessments included questions on asthma symptoms, night-time awakenings, and rescue medication use. The total daily asthma symptom score was a composite of the morning and evening responses, scored on a 0 to 6 scale. Greater scores indicated a greater burden of symptoms. The electronic patient-reported outcomes devices were programmed to alert patients and study centers when specific criteria were met for asthma worsening on ≥2 consecutive days/nights, including a decrease in morning peak expiratory flow of ≥30% compared with baseline, a ≥50% increase in rescue medication use or 1 new β₂-agonist nebuliser compared with the previous 7 days, nocturnal awakening because of asthma that required rescue medication use, and an increase in total asthma symptom score of ≥2 units above the screening average (or the maximum possible daily score of 6). Safety outcomes included adverse events and serious adverse events.

The primary analysis population for this subgroup analysis comprised Korean patients with baseline blood eosinophil counts ≥ 300 cells/µL in the overall SIROCCO trial. Efficacy data are not presented for the population with eosinophil counts < 300 cells/μL because of the small sample size. Annual exacerbation rates were estimated using a negative binomial model that included treatment, number of exacerbations in the previous year, and use of maintenance OCS as covariates. Least squares mean changes from baseline in FEV1 compared with placebo were estimated using a mixed-effects model for repeated measures analysis, with adjustment for treatment, baseline prebronchodilator FEV1, use of maintenance OCS, visit, and visit by treatment interaction. Least squares mean changes from baseline in biweekly average total asthma symptom score compared with placebo were also estimated using a mixed-effects model for repeated measures analysis, with adjustment for treatment, baseline total asthma symptom score, use of maintenance OCS, visit, and visit by treatment interaction. Because these analyses were not part of the formal testing strategy, all P values were nominal. Adverse events were summarized using descriptive statistics. All data analyses were conducted using SAS system version 9.2 or later (SAS Institute Inc., Cary, NC, USA).

Overall, 2,681 patients participated in the SIROCCO trial. Of these, 177 were Korean, with 122 randomly assigned to receive benralizumab or placebo (Fig. 2). Treatment was completed by 116 Korean patients, with 115 completing the trial. The most common reasons for treatment discontinuation (3 patients) and trial discontinuation (2 patients) were adverse events.

The mean (standard deviation) number of exacerbations experienced in the year before the trial was 3.6 (2.8), 3.1 (2.0), and 2.7 (1.1) for Korean patients receiving placebo, benralizumab Q4W, and benralizumab Q8W, respectively, compared with 2.9 (1.7) for the overall SIROCCO trial population (Table 1). Baseline demographics and clinical characteristics were similar between cohorts; however, the placebo group had more frequent OCS use and decreased lung function compared with the other cohorts, and the placebo and benralizumab Q4W cohorts had greater blood eosinophil counts than the Q8W cohort and overall SIROCCO trial population.

This analysis included Korean patients receiving high-dosage ICS/LABA with baseline blood eosinophil counts ≥ 300 cells/µL. Benralizumab reduced the annual asthma exacerbation rate by 70% with the Q4W regimen (rate 0.79 [95% confidence interval {CI}, 0.43–1.46], rate ratio 0.30 [95% CI, 0.13–0.65], nominal P = 0.003; n = 28) and by 85% with the Q8W regimen (rate 0.40 [95% CI, 0.19–0.82], rate ratio 0.15 [95% CI, 0.06–0.36], nominal P < 0.001; n = 30) compared with placebo (rate 2.67 [95% CI, 1.61–4.42]; n = 28) (Fig. 3 and Table 2). Prebronchodilator FEV1 increased with benralizumab by 0.270 L (Q4W: 95% CI, 0.039–0.500, nominal P = 0.023; n = 28) and 0.362 L (Q8W: 95% CI, 0.143–0.582, nominal P = 0.002; n = 30) relative to placebo (n = 27) at week 48 from baseline (Fig. 4 and Table 2). Improvements in FEV1 with benralizumab vs. placebo were observed as early as 4 weeks after treatment and were maintained throughout the study (Fig. 4). Total asthma symptom score was similar for both benralizumab Q4W (−0.27 [95% CI, −0.83 to 0.30], nominal P = 0.356; n = 27) and benralizumab Q8W (0.10 [95% CI, −0.44 to 0.65], nominal P = 0.708; n = 30) compared with placebo (n = 28) at week 48 from baseline (Fig. 5 and Table 2).

Overall, 100 of the 122 (82%) Korean patients experienced 1 or more adverse events (Table 3). The most common adverse events were upper respiratory tract infection (38 patients) and nasopharyngitis (26 patients). The majority of adverse events were not considered related to benralizumab treatment. Adverse events resulting in discontinuation of treatment occurred in 2 patients who received benralizumab (both Q4W, asthenia and cerebral hemorrhage) and 1 patient who received placebo (injection site erythema). Serious adverse events were reported for 9 patients who received benralizumab compared with 11 who received placebo. One patient who received benralizumab Q4W died from cerebral hemorrhage, which was considered to be not related to treatment.