布地奈德/格隆溴铵/富马酸福莫特罗二水合物治疗未控制哮喘（KALOS 与 LOGOS 研究）：两项配对多中心、双盲、双模
2026/04/02
摘要
背景：对于控制不佳的哮喘患者，可在吸入性糖皮质激素（ICS）/长效β2受体激动剂（LABA）治疗基础上联用长效抗胆碱能拮抗剂（LAMA）。
目的：本研究旨在评估布地奈德/格隆溴铵/富马酸福莫特罗二水合物（BGF），对比采用 Aerosphere共悬浮递送技术的布地奈德/富马酸福莫特罗二水合物（BFFA）以及现有混悬制剂（信必可，BFFS）的有效性与安全性。
方法：本研究开展两项多中心、随机、双盲、双模拟3期研究（KALOS与LOGOS）。KALOS研究纳入20个国家378个中心，LOGOS研究纳入15个国家324个中心，招募年龄12～80岁、每日使用中剂量或高剂量ICS-LABA治疗后哮喘仍控制不佳的受试者。受试者按1:1:1:1随机分配至以下各组，经加压定量吸入器每日2次给药，持续24～52周：BGF 320μg、28.8μg、10μg 组（BGF 28.8）；BGF 320μg、14.4μg、10μg 组（BGF 14.4）；BFFA 320μg、10μg 组；或 BFFS 320μg、9μg 组。主要肺功能终点为0～3小时第一秒用力呼气容积曲线下面积（FEV1 AUC0-3）较基线的变化，以及第1天至第24周晨间给药前谷值FEV1较基线的变化（观察24周，依据各国药监部门指导原则）。两项研究的主要合并分析终点为年化重度急性加重率。有效性分析集与安全性分析集均包含所有随机分配且接受任意剂量研究药物的受试者，分别按随机分配治疗组与实际接受治疗组进行分析。KALOS与 LOGOS研究已在 ClinicalTrials.gov注册（注册号分别为NCT04609878和 NCT04609904），且研究已完成。
结果：KALOS 研究入组时间为 2020年12月15日至 2025年3月21日，LOGOS 研究为 2021 年3月1日至2025年3月20日，共招募8820例受试者，其中4311例接受治疗：BGF 28.8 组1179例、BGF 14.4组726例、BFFA组1210例、BFFS组1196例。各研究中，所有用于注册申报比较的预设多重性校正主要终点均达到。所有比较中，BGF 28.8 组谷值FEV1 及FEV1 AUC0-3较基线变化的最小二乘均数差异均优于对照组（均P<0.05）。BGF 28.8 组对比 BFF 联合组（BFFcombined）治疗 24 周后，晨间给药前谷值 FEV₁较基线变化的最小二乘均数差为76 mL（95% CI 57～94；P<0.0001），FEV1 AUC0-3较基线变化的最小二乘均数差为90 mL（95% CI 72～108；P<0.0001）。与 BFF 联合组相比，BGF 28.8 组重度急性加重率降低（发生率比0.86，95% CI 0.76～0.97；P=0.012）；与 BFFS 组相比，急性加重率亦降低（发生率比0.82，95% CI 0.71～0.94；P=0.0043）。BGF 28.8 组对比 BFFA 组的急性加重发生率比为0.90（95% CI 0.78～1.03；P=0.12）。BGF 28.8组、BGF 14.4组、BFFA组、BFFS组的不良事件发生率分别为 53.2%（627例）、60.0%（436例）、55.2%（666例）、58.4%（698例），无治疗相关死亡事件。
结论：上述结果表明，对于使用中高剂量ICS-LABA治疗后哮喘仍控制不佳的广泛人群，BGF可改善肺功能并降低重度急性加重率。无论受试者近期有无急性加重史均可观察到该获益，提示BGF可为未控制哮喘患者带来获益，且无需在升级治疗前先出现ICS-LABA治疗下的急性加重事件。
Budesonide-glycopyrronium-formoterol fumarate dihydrate in uncontrolled asthma (KALOS and LOGOS): twin multicentre, double-blind, double-dummy, parallel-group, randomised, phase 3 trials.
Papi A, Wise RA, Jackson DJ, Lugogo N, Chen R, Trasieva T, Obasi C, Movitz C, Helman J, Salter P, Springer K, Bondoc M, Shah M, Knappenberger K, Bowen K, Pandya H, Megally A, Patel M; KALOS and LOGOS study investigators.
Abstract
BACKGROUND:Long-acting muscarinic antagonists (LAMA) can be added to inhaled corticosteroid- (ICS)-long-acting β2-agonist (LABA) therapy for inadequately controlled asthma.
OBJECTIVE:We aimed to evaluate the efficacy and safety of budesonide-glycopyrronium-formoterol fumarate dihydrate (BGF) versus budesonide-formoterol fumarate dihydrate using Aerosphere co-suspension delivery technology (BFFA) and the current suspension formulation (Symbicort, BFFS).
METHODS:Two multicentre, randomised, double-blind, double-dummy, phase 3 studies (KALOS and LOGOS) recruited participants aged 12-80 years with inadequately-controlled asthma despite daily medium-dose or high-dose ICS-LABA use from across 378 sites in 20 countries (KALOS), and 324 sites in 15 countries (LOGOS). Participants were randomly assigned (1:1:1:1) to BGF 320μg, 28.8μg, 10 μg (BGF 28.8); BGF 320μg, 14.4 μg, 10μg (BGF 14.4); BFFA 320μg, 10 μg; or BFFS 320μg, 9μg, twice a day via pressurised metered-dose inhaler for 24-52 weeks. Primary lung function endpoints were change from baseline in FEV1 area under the curve from 0 h to 3 h (AUC0-3) and in morning pre-dose trough FEV1 from day 1 to week 24 (over 24 weeks; depending on regional health authority guidance). The primary pooled analysis across both studies was annualised severe exacerbations. The efficacy analysis set and safety set included all randomly assigned participants receiving any amount of study treatment but were analysed according to randomly assigned treatment and received treatment, respectively. The KALOS and LOGOS studies are registered with ClinicalTrials.gov (NCT04609878 and NCT04609904, respectively) and are complete.
RESULTS:Between Dec 15, 2020, and March 21, 2025 (KALOS), and between March 1, 2021, and March 20, 2025 (LOGOS), 8820 participants were recruited and 4311 received treatment (1179 received BGF 28.8, 726 received BGF 14.4, 1210 received BFFA, and 1196 received BFFS). In each study, the pre-specified multiplicity-adjusted primary endpoints for all regulatory comparisons were met. Least squares mean differences favoured BGF 28.8 for change from baseline in trough FEV1 and FEV1 AUC0-3 across all comparisons (all p<0.05). Least squares mean differences in change from baseline in morning pre-dose trough FEV1 and in FEV1 AUC0-3 over 24 weeks for BGF 28.8 versus BFFcombined were 76 mL (95% CI 57-94; p<0.0001) and 90 mL (72-108; p<0.0001), respectively. BGF 28.8 reduced severe exacerbation rates versus BFFcombined (incidence rate ratio 0.86, 95% CI 0.76-0.97; p=0.012) and versus BFFS (0.82, 0.71-0.94; p=0.0043). Exacerbation rate ratio for BGF 28.8 versus BFFA was 0.90 (95% CI 0.78-1.03; p=0.12). 627 (53.2%) adverse events were observed with BGF 28.8, 436 (60.0%) with BGF 14.4, 666 (55.2%) with BFFA, and 698 (58.4%) with BFFS. No deaths were treatment related.
CONCLUSION:These findings show that BGF improves lung function and reduces severe exacerbation rates in a broad population with asthma inadequately controlled despite medium-dose or high-dose ICS-LABA use. Given that these findings were observed regardless of recent exacerbation history, BGF could benefit individuals with inadequately controlled asthma without requiring a recent episode of acute deterioration on ICS-LABA before escalation.
背景：对于控制不佳的哮喘患者，可在吸入性糖皮质激素（ICS）/长效β2受体激动剂（LABA）治疗基础上联用长效抗胆碱能拮抗剂（LAMA）。
目的：本研究旨在评估布地奈德/格隆溴铵/富马酸福莫特罗二水合物（BGF），对比采用 Aerosphere共悬浮递送技术的布地奈德/富马酸福莫特罗二水合物（BFFA）以及现有混悬制剂（信必可，BFFS）的有效性与安全性。
方法：本研究开展两项多中心、随机、双盲、双模拟3期研究（KALOS与LOGOS）。KALOS研究纳入20个国家378个中心，LOGOS研究纳入15个国家324个中心，招募年龄12～80岁、每日使用中剂量或高剂量ICS-LABA治疗后哮喘仍控制不佳的受试者。受试者按1:1:1:1随机分配至以下各组，经加压定量吸入器每日2次给药，持续24～52周：BGF 320μg、28.8μg、10μg 组（BGF 28.8）；BGF 320μg、14.4μg、10μg 组（BGF 14.4）；BFFA 320μg、10μg 组；或 BFFS 320μg、9μg 组。主要肺功能终点为0～3小时第一秒用力呼气容积曲线下面积（FEV1 AUC0-3）较基线的变化，以及第1天至第24周晨间给药前谷值FEV1较基线的变化（观察24周，依据各国药监部门指导原则）。两项研究的主要合并分析终点为年化重度急性加重率。有效性分析集与安全性分析集均包含所有随机分配且接受任意剂量研究药物的受试者，分别按随机分配治疗组与实际接受治疗组进行分析。KALOS与 LOGOS研究已在 ClinicalTrials.gov注册（注册号分别为NCT04609878和 NCT04609904），且研究已完成。
结果：KALOS 研究入组时间为 2020年12月15日至 2025年3月21日，LOGOS 研究为 2021 年3月1日至2025年3月20日，共招募8820例受试者，其中4311例接受治疗：BGF 28.8 组1179例、BGF 14.4组726例、BFFA组1210例、BFFS组1196例。各研究中，所有用于注册申报比较的预设多重性校正主要终点均达到。所有比较中，BGF 28.8 组谷值FEV1 及FEV1 AUC0-3较基线变化的最小二乘均数差异均优于对照组（均P<0.05）。BGF 28.8 组对比 BFF 联合组（BFFcombined）治疗 24 周后，晨间给药前谷值 FEV₁较基线变化的最小二乘均数差为76 mL（95% CI 57～94；P<0.0001），FEV1 AUC0-3较基线变化的最小二乘均数差为90 mL（95% CI 72～108；P<0.0001）。与 BFF 联合组相比，BGF 28.8 组重度急性加重率降低（发生率比0.86，95% CI 0.76～0.97；P=0.012）；与 BFFS 组相比，急性加重率亦降低（发生率比0.82，95% CI 0.71～0.94；P=0.0043）。BGF 28.8 组对比 BFFA 组的急性加重发生率比为0.90（95% CI 0.78～1.03；P=0.12）。BGF 28.8组、BGF 14.4组、BFFA组、BFFS组的不良事件发生率分别为 53.2%（627例）、60.0%（436例）、55.2%（666例）、58.4%（698例），无治疗相关死亡事件。
结论：上述结果表明，对于使用中高剂量ICS-LABA治疗后哮喘仍控制不佳的广泛人群，BGF可改善肺功能并降低重度急性加重率。无论受试者近期有无急性加重史均可观察到该获益，提示BGF可为未控制哮喘患者带来获益，且无需在升级治疗前先出现ICS-LABA治疗下的急性加重事件。
（中日友好医院呼吸与危重症医学科 张婧媛 摘译 林江涛 审校）
（Lancet Respir Med. 2026 Feb 12:S2213-2600(25)00457-6. doi: 10.1016/S2213-2600(25)00457-6.）
（Lancet Respir Med. 2026 Feb 12:S2213-2600(25)00457-6. doi: 10.1016/S2213-2600(25)00457-6.）
Budesonide-glycopyrronium-formoterol fumarate dihydrate in uncontrolled asthma (KALOS and LOGOS): twin multicentre, double-blind, double-dummy, parallel-group, randomised, phase 3 trials.
Papi A, Wise RA, Jackson DJ, Lugogo N, Chen R, Trasieva T, Obasi C, Movitz C, Helman J, Salter P, Springer K, Bondoc M, Shah M, Knappenberger K, Bowen K, Pandya H, Megally A, Patel M; KALOS and LOGOS study investigators.
Abstract
BACKGROUND:Long-acting muscarinic antagonists (LAMA) can be added to inhaled corticosteroid- (ICS)-long-acting β2-agonist (LABA) therapy for inadequately controlled asthma.
OBJECTIVE:We aimed to evaluate the efficacy and safety of budesonide-glycopyrronium-formoterol fumarate dihydrate (BGF) versus budesonide-formoterol fumarate dihydrate using Aerosphere co-suspension delivery technology (BFFA) and the current suspension formulation (Symbicort, BFFS).
METHODS:Two multicentre, randomised, double-blind, double-dummy, phase 3 studies (KALOS and LOGOS) recruited participants aged 12-80 years with inadequately-controlled asthma despite daily medium-dose or high-dose ICS-LABA use from across 378 sites in 20 countries (KALOS), and 324 sites in 15 countries (LOGOS). Participants were randomly assigned (1:1:1:1) to BGF 320μg, 28.8μg, 10 μg (BGF 28.8); BGF 320μg, 14.4 μg, 10μg (BGF 14.4); BFFA 320μg, 10 μg; or BFFS 320μg, 9μg, twice a day via pressurised metered-dose inhaler for 24-52 weeks. Primary lung function endpoints were change from baseline in FEV1 area under the curve from 0 h to 3 h (AUC0-3) and in morning pre-dose trough FEV1 from day 1 to week 24 (over 24 weeks; depending on regional health authority guidance). The primary pooled analysis across both studies was annualised severe exacerbations. The efficacy analysis set and safety set included all randomly assigned participants receiving any amount of study treatment but were analysed according to randomly assigned treatment and received treatment, respectively. The KALOS and LOGOS studies are registered with ClinicalTrials.gov (NCT04609878 and NCT04609904, respectively) and are complete.
RESULTS:Between Dec 15, 2020, and March 21, 2025 (KALOS), and between March 1, 2021, and March 20, 2025 (LOGOS), 8820 participants were recruited and 4311 received treatment (1179 received BGF 28.8, 726 received BGF 14.4, 1210 received BFFA, and 1196 received BFFS). In each study, the pre-specified multiplicity-adjusted primary endpoints for all regulatory comparisons were met. Least squares mean differences favoured BGF 28.8 for change from baseline in trough FEV1 and FEV1 AUC0-3 across all comparisons (all p<0.05). Least squares mean differences in change from baseline in morning pre-dose trough FEV1 and in FEV1 AUC0-3 over 24 weeks for BGF 28.8 versus BFFcombined were 76 mL (95% CI 57-94; p<0.0001) and 90 mL (72-108; p<0.0001), respectively. BGF 28.8 reduced severe exacerbation rates versus BFFcombined (incidence rate ratio 0.86, 95% CI 0.76-0.97; p=0.012) and versus BFFS (0.82, 0.71-0.94; p=0.0043). Exacerbation rate ratio for BGF 28.8 versus BFFA was 0.90 (95% CI 0.78-1.03; p=0.12). 627 (53.2%) adverse events were observed with BGF 28.8, 436 (60.0%) with BGF 14.4, 666 (55.2%) with BFFA, and 698 (58.4%) with BFFS. No deaths were treatment related.
CONCLUSION:These findings show that BGF improves lung function and reduces severe exacerbation rates in a broad population with asthma inadequately controlled despite medium-dose or high-dose ICS-LABA use. Given that these findings were observed regardless of recent exacerbation history, BGF could benefit individuals with inadequately controlled asthma without requiring a recent episode of acute deterioration on ICS-LABA before escalation.
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