In the Phase III KRONOS study, triple therapy with budesonide/glycopyrronium/formoterol fumarate metered dose inhaler (BGF MDI) was shown to reduce exacerbations and improve lung function versus glycopyrronium/formoterol fumarate dihydrate (GFF) MDI in patients with moderate-to-very severe chronic obstructive pulmonary disease (COPD). However, whether the benefits related to the ICS component of BGF are driven by patients with high blood eosinophil counts (EOS) and/or airway reversibility has not been previously studied. KRONOS was a Phase III, double-blind, parallel-group, multicenter, randomized, controlled study of patients with moderate-to-very-severe COPD. Patients were randomized 2:2:1:1 to receive BGF 320/14.4/10 μg, GFF 14.4/10 μg, budesonide/formoterol fumarate dihydrate (BFF) MDI 320/10 μg via a single Aerosphere inhaler, or open-label budesonide/formoterol fumarate dihydrate dry powder inhaler 400/12 μg (BUD/FORM DPI; Symbicort Turbuhaler) twice-daily for 24 weeks. Efficacy outcomes included in this post-hoc analysis were change from baseline in morning pre-dose trough FEV1 over weeks 12–24 and the rate of moderate-to-severe and severe COPD exacerbations. Adverse events in the non-reversible subgroup are also reported. Of 1896 patients analyzed, 948 (50%) were non-reversible and had EOS < 300 cells/mm3. In this group, BGF significantly improved morning pre-dose trough FEV1 versus BFF and BUD/FORM (least squares mean treatment difference, 95% confidence interval [CI] 69 mL [39, 99], unadjusted p < 0.0001 and 51 mL [20, 81], unadjusted p = 0.0011, respectively) and was comparable to GFF. BGF also significantly reduced annual moderate-to-severe exacerbation rates versus GFF (rate ratio [95% CI] 0.53 [0.37, 0.76], unadjusted p = 0.0005), with numerical reductions observed versus BFF and BUD/FORM. These results were similar for the overall study population. Safety findings were generally similar between non-reversible patients with EOS < 300 cells/mm3 and the overall population. In patients with moderate-to-very-severe COPD without airway reversibility and EOS < 300 cells/mm3, BGF significantly improved morning pre-dose trough FEV1 versus BFF and BUD/FORM and significantly reduced the rate of moderate-to-severe exacerbations versus GFF. These findings demonstrate that BGF can provide benefits for a broad range of patients with COPD, and that the overall findings of the KRONOS primary analysis were not driven by patients with reversible airflow obstruction or high eosinophil counts. Trial registration ClinicalTrials.gov, NCT02497001. Registered 14 July 2015, https://clinicaltrials.gov/ct2/show/NCT02497001

中文翻译：

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布地奈德/格隆溴铵/福莫特罗计量吸入器在 COPD 患者中的疗效：来自 KRONOS 研究的事后分析，排除了气道可逆性和嗜酸性粒细胞计数高的患者

在 III 期 KRONOS 研究中，与格隆溴铵/富马酸福莫特罗二水合物 (GFF) MDI 相比，布地奈德/格隆溴铵/富马酸福莫特罗计量吸入器 (BGF MDI) 三联疗法显示可减少病情加重并改善肺功能。严重的慢性阻塞性肺疾病（COPD）。然而，先前尚未研究与 BGF 的 ICS 成分相关的益处是否由高血嗜酸性粒细胞计数 (EOS) 和/或气道可逆性患者驱动。KRONOS 是一项针对中度至极重度 COPD 患者的 III 期、双盲、平行组、多中心、随机、对照研究。患者以 2:2:1:1 的比例随机接受 BGF 320/14.4/10 μg、GFF 14.4/10 μg、布地奈德/富马酸福莫特罗二水合物 (BFF) MDI 320/10 μg，通过单个 Aerosphere 吸入器，或开放标签布地奈德/富马酸福莫特罗二水合物干粉吸入器 400/12 μg（BUD/FORM DPI；Symbicort Turbuhaler），每天两次，持续 24 周。此事后分析中包括的疗效结果是第 12-24 周内早晨给药前的 FEV1 谷值与基线的变化以及中度至重度和重度 COPD 急性加重的发生率。还报告了不可逆亚组中的不良事件。在分析的 1896 名患者中，948 名 (50%) 是不可逆的，并且 EOS < 300 个细胞/mm3。在该组中，与 BFF 和 BUD/FORM 相比，BGF 显着改善了早晨给药前的 FEV1 谷值（最小二乘平均治疗差异，95% 置信区间 [CI] 69 mL [39, 99]，未调整的 p < 0.0001 和 51 mL [20 , 81]，未调整的 p = 0.0011，分别）并且与 GFF 相当。与 GFF 相比，BGF 还显着降低了年度中度至重度恶化率（比率 [95% CI] 0.53 [0.37, 0.76]，未调整 p = 0.0005），与 BFF 和 BUD/FORM 相比观察到数值降低。对于整个研究人群，这些结果是相似的。EOS < 300 个细胞/mm3 的不可逆患者和总体人群的安全性结果通常相似。在没有气道可逆性和 EOS < 300 细胞/mm3 的中度至极重度 COPD 患者中，与 BFF 和 BUD/FORM 相比，BGF 显着改善了早晨给药前的 FEV1 谷值，并显着降低了中度至重度急性加重的发生率。 GFF。这些发现表明 BGF 可以为广泛的 COPD 患者提供益处，并且 KRONOS 主要分析的总体结果不是由具有可逆气流阻塞或高嗜酸性粒细胞计数的患者驱动的。试验注册 ClinicalTrials.gov，NCT02497001。2015 年 7 月 14 日注册，https://clinicaltrials.gov/ct2/show/NCT02497001