Budesonide-glycopyrronium-formoterol fumarate dihydrate in uncontrolled asthma (KALOS and LOGOS): twin multicentre, double-blind, double-dummy, parallel-group, randomised, phase 3 trials.

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).

我们旨在评估布地奈德-甘珀索-福莫特罗富马酸二水合物（BGF）与采用Aerosphere共悬浮输送技术的布地奈德-福莫特罗富马酸二水合物（BFFA）以及现行悬浮制剂（Symbicort, BFFS）在疗效和安全性方面的比较。

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).

两项多中心、随机、双盲、双模拟的III期研究（KALOS和LOGOS）招募了年龄在12-80岁之间，尽管每天使用中等剂量或高剂量ICS-LABA治疗，但哮喘控制不佳的参与者，研究地点覆盖20个国家的378个中心（KALOS），以及15个国家的324个中心（LOGOS）。

Participants were randomly assigned (1:1:1:1) to BGF 320 μg, 28·8 μg, 10 μg (BGF 28·8); BGF 320 μg, 14·4 μg, 10 μg (BGF 14·4); BFFA 320 μg, 10 μg; or BFFS 320 μg, 9 μg, twice a day via pressurised metered-dose inhaler for 24-52 weeks.

参与者被随机分配（1:1:1:1）接受BGF 320 μg, 28·8 μg, 10 μg（BGF 28·8）；BGF 320 μg, 14·4 μg, 10 μg（BGF 14·4）；BFFA 320 μg, 10 μg；或BFFS 320 μg, 9 μg，每天两次通过加压定量吸入器吸入，持续24-52周。

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).

主要的肺功能终点是基线至3小时内的第一秒用力呼气量（FEV1）曲线下面积（AUC0-3）的变化，以及从第1天至第24周（24周内；根据地区卫生当局的指导）早晨用药前FEV1的谷值变化。

The primary pooled analysis across both studies was annualised severe exacerbations.

两项研究的综合主要分析是年度严重急性发作次数。

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.

疗效分析集和安全性集包括所有随机分配的参与者，这些参与者接受了任何数量的研究治疗，但分别根据随机分配的治疗和接受的治疗进行分析。

The KALOS and LOGOS studies are registered with ClinicalTrials.gov (NCT04609878 and NCT04609904, respectively) and are complete.

KALOS和LOGOS研究已在ClinicalTrials.gov注册（分别为NCT04609878和NCT04609904），且研究已完成。

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).

在2020年12月15日至2025年3月21日（KALOS研究）以及2021年3月1日至2025年3月20日（LOGOS研究）期间，共招募了8820名参与者，其中4311人接受了治疗（1179人接受了BGF 28·8，726人接受了BGF 14·4，1210人接受了BFFA，1196人接受了BFFS）。

In each study, the pre-specified multiplicity-adjusted primary endpoints for all regulatory comparisons were met.

在每项研究中，所有规定的事先调整多重性的一级终点均达到了监管比较的要求。

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).

最小二乘均值差异在所有比较中均有利于BGF 28·8，其基线至谷值的FEV1和FEV1 AUC0-3的变化（所有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与BFFcombined相比，24周内早晨用药前谷值FEV1和FEV1 AUC0-3的基线变化的最小二乘均值差异分别为76毫升（95%置信区间57-94；p<0·0001）和90毫升（72-108；p<0·0001）。

BGF 28·8 reduced severe exacerbation rates versus BFFcombined (incidencerate ratio 0·86, 95% CI 0·76-0·97; p=0·012) and versus BFFS (0·82, 0·71-0·94; p=0·0043).

BGF 28·8 降低了严重急性加重率，与 BFFcombined 相比（发生率比为 0·86，95% 置信区间 0·76-0·97；p=0·012），与 BFFS 相比（发生率比为 0·82，95% 置信区间 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.

BGF 28·8 与 BFFA 相比，急性加重率比为 0·90（95% 置信区间 0·78-1·03；p=0·12）。观察到 BGF 28·8 有 627（53·2%）例不良事件，BGF 14·4 有 436（60·0%）例，BFFA 有 666（55·2%）例，BFFS 有 698（58·4%）例。

No deaths were treatment related.

没有与治疗相关的死亡事件。

interpretation

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.

这些发现表明，对于尽管使用中等剂量或高剂量ICS-LABA但仍控制不佳的广泛哮喘人群，BGF能够改善肺功能并降低严重急性加重率。

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.

鉴于这些发现是在不考虑近期加重病史的情况下观察到的，BGF可能对那些哮喘控制不充分的个体有益，而无需在升级治疗前在ICS-LABA上经历近期的急性恶化事件。

funding

AstraZeneca.

阿斯利康。