Department of Respiratory Medicine, Nara Medical University Graduate School of Medicine, 840 Shijo-cho, Kashihara-shi, Nara, 634-8521, Japan.
Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
Respir Res. 2021 Jun 28;22(1):187. doi: 10.1186/s12931-021-01773-1.
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 FEV 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/mm. In this group, BGF significantly improved morning pre-dose trough FEV 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/mm and the overall population.
In patients with moderate-to-very-severe COPD without airway reversibility and EOS < 300 cells/mm, BGF significantly improved morning pre-dose trough FEV 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.
在 III 期 KRONOS 研究中，与甘精福莫特罗双相气雾剂（GFF）相比，布地奈德/格隆溴铵/富马酸福莫特罗干粉吸入剂（BGF）三联疗法可减少中重度至极重度慢性阻塞性肺疾病（COPD）患者的恶化并改善肺功能。然而，BGF 中 ICS 成分的益处是否与高血嗜酸性粒细胞计数（EOS）和/或气道可逆性有关尚未得到研究。
KRONOS 是一项 III 期、双盲、平行分组、多中心、随机、对照研究，纳入中重度至极重度 COPD 患者。患者按 2:2:1:1 的比例随机分配接受 BGF 320/14.4/10μg、GFF 14.4/10μg、布地奈德/福莫特罗双相气雾剂（BFF）MDI 320/10μg（通过 Aerosphere 吸入器）或布地奈德/福莫特罗双相气雾剂干粉吸入剂（BUD/FORM DPI；Symbicort Turbuhaler）400/12μg （BUD/FORM DPI；Symbicort Turbuhaler），每日 2 次，持续 24 周。本事后分析的疗效结局包括第 12-24 周清晨预剂量谷值 FEV 的变化和中重度至重度 COPD 恶化的发生率。还报告了不可逆亚组的不良事件。
在分析的 1896 例患者中，948 例（50%）为不可逆患者，EOS<300 个细胞/mm。在该组中，与 BFF 和 BUD/FORM 相比，BGF 显著改善清晨预剂量谷值 FEV（最小二乘均数治疗差异，95%置信区间 [CI] 69mL[39，99]，未调整 p<0.0001 和 51mL[20，81]，未调整 p=0.0011），与 GFF 相当。BGF 还显著降低了与 GFF 相比的中重度恶化发生率（率比[95%CI]0.53[0.37，0.76]，未调整 p=0.0005），与 BFF 和 BUD/FORM 相比，也观察到数值降低。这些结果在总体研究人群中相似。不可逆患者与 EOS<300 个细胞/mm 的患者与总体人群的安全性发现基本相似。
在中重度至极重度 COPD 且无气道可逆性和 EOS<300 个细胞/mm 的患者中，与 BFF 和 BUD/FORM 相比，BGF 显著改善清晨预剂量谷值 FEV，并显著降低中重度恶化的发生率与 GFF 相比。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受可逆性气流阻塞或高嗜酸性粒细胞计数患者的影响。试验注册ClinicalTrials.gov，NCT02497001。2015 年 7 月 14 日注册，https://clinicaltrials.gov/ct2/show/NCT02497001。
