每日一次莫米松加吲达特罗与莫米松或每日两次氟替卡松加沙美特罗治疗哮喘控制不佳患者的比较(PALLADIUM)：一项随机、
2020/08/20
每日一次莫米松加吲达特罗与莫米松或每日两次氟替卡松加沙美特罗治疗哮喘控制不佳患者的比较(PALLADIUM)：一项随机、双盲、三模拟、对照的3期研究
摘要
背景：吸入皮质类固醇(ICS)和长效β2肾上腺素受体激动剂(LABA)的固定剂量组合(FDCs)在哮喘治疗中被认为是安全和有效的。大多数可用的FDCs需要每天两次剂量才能达到最佳的治疗效果。PALLADIUM研究的目的是评估每日一次的糠酸莫米松加醋酸吲达特罗(MF-IND)FDC与单用糠酸莫米松(MF)治疗哮喘控制不佳患者的有效性和安全性。
方法：这项为期52周的双盲、三模拟、平行组3期研究从24个国家的316个中心招募患者。纳入患者年龄为12-75岁，哮喘确诊至少1年，预计FEV1%为50-85%，哮喘控制问卷7分至少为1.5分包括接受中高剂量ICS或低剂量ICS+LABA治疗。哮喘加重史本研究不要求。参与者通过互动反应技术被随机分配（1：1：1：1：1）接受以下治疗之一，为期52周：通过Breezhaler吸入高剂量MF-IND（320μg，150μg）或中剂量MF-IND（160μg，150μg）每日一次；通过Twithaler吸入高剂量MF（800μg（每日两次400μg））或中剂量MF（每日一次400μg）；或通过Diskus吸入高剂量丙酸氟替卡松沙美特罗（FLU-SAL；500μg，50μg）每日两次。参与者在早上和晚上适当地通过Breezhaler，Twisthaler或Diskus设备吸入安慰剂。主要终点是在26周时，高剂量和中剂量MF-IND与各自的MF剂量相比较基线FEV1值的改善，在全分析数据集中通过混合模型重复测量分析。将每日一次的高剂量MF-IND与每日两次的高剂量FLU-SAL在改善第26周时的FEV1值方面的非劣效性进行比较，使用混合模型重复测量作为次要终点之一。对所有接受过至少一剂研究药物的患者进行安全性评估。这项研究已在ClinicalTrials.gov注册，NCT02554786，并已完成。
结果：2015年12月29日至2018年5月4日，2216名患者被随机分配（高剂量MF-IND，n=445；中剂量MF-IND，n=439；高剂量MF，n=442；中剂量MF，n=444；高剂量FLU-SAL，n=446），其中1973例（89.0%）完成研究治疗，234例（10.6%）提前中断研究治疗。高剂量MF-IND（治疗差异[Δ]132mL[95%可信区间88～176]；p<0.001）和中剂量MF-IND（Δ211mL[167～255]；p<0.001）在26周时改善FEV1值方面优于相应剂量的MF。在26周时，高剂量MF-IND在改善FEV1方面不逊于高剂量FLU-SAL（Δ为36mL[-7～80]；p=0.101）。总之，各治疗组的不良事件发生率相似。
结论：在第26周，每天一次的ICS和LABA的FDC（MF-IND）较ICS单一疗法（MF）显著改善肺功能，高剂量 MF-IND改善FEV1的效果不亚于每天两次ICS和LABA的联合用药(高剂量FlU-SAL)。MF-IND的组合为哮喘控制提供了一种每天一次的新型干粉选择。
(中日友好医院呼吸与危重症医学科 王瑞茵 摘译 林江涛 审校)
(Lancet Respir Med. 2020 Jul 9;S2213-2600(20)30178-8.)
(Lancet Respir Med. 2020 Jul 9;S2213-2600(20)30178-8.)
Once-daily mometasone plus indacaterol versus mometasone or twice-daily fluticasone plus salmeterol in patients with inadequately controlled asthma (PALLADIUM): a randomised, double-blind, triple-dummy, controlled phase 3 study.
Richard N van Zyl-Smit, Matthias Krüll, Christian Gessner, Yasuhiro Gon, Oliver Noga, Alexia Richard, Amy de Los Reyes, Xu Shu, Abhijit Pethe, Ana-Maria Tanase, Peter D'Andrea, PALLADIUM trial investigators.
Abstract
BACKGROUND:Fixed-dose combinations (FDCs) of inhaled corticosteroids (ICS) and long-acting β2-adrenoceptor agonists (LABA) are considered safe and efficacious in asthma management. Most available FDCs require twice-daily dosing to achieve optimum therapeutic effect. The objective of the PALLADIUM study was to assess the efficacy and safety of once-daily FDC of mometasone furoate plus indacaterol acetate (MF-IND) versus mometasone furoate (MF) monotherapy in patients with inadequately controlled asthma.
METHODS:This 52-week, double-blind, triple-dummy, parallel-group, phase 3 study recruited patients from 316 centres across 24 countries. Patients aged 12 to 75 years with a documented diagnosis of asthma for at least 1 year, percentage of predicted FEV1 of 50-85%, and an Asthma Control Questionnaire 7 score of at least 1·5 despite treatment with medium-dose or high-dose ICS or low-dose ICS plus LABA were included. A history of asthma exacerbations was not a study requirement. Participants were randomily assigned (1:1:1:1:1) via interactive response technology to receive one of the following treatments for 52 weeks: high-dose MF-IND (320 μg, 150 μg) or medium-dose MF-IND (160 μg, 150 μg) once daily via Breezhaler; high-dose MF (800 μg [400 μg twice daily]) or medium-dose MF (400 μg once daily) via Twisthaler; or high-dose fluticasone propionate-salmeterol xinafoate (FLU-SAL; 500 μg, 50 μg) twice daily via Diskus. Participants received placebo via inhalation through the Breezhaler, Twisthaler, or Diskus devices in the mornings and evenings, as appropriate. The primary endpoint was improvement in trough FEV1 with high-dose and medium-dose MF-IND versus respective MF doses from baseline at 26 weeks, analysed in the full analysis set by means of a mixed model for repeated measures. High-dose MF-IND once daily was compared with high-dose FLU-SAL twice daily for non-inferiority on improving trough FEV1 at week 26 with a margin of -90 mL using mixed model for repeated measures as one of the secondary endpoints. Safety was assessed in all patients who had received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT02554786, and is completed.
RESULTS:Between Dec 29, 2015, and May 4, 2018, 2216 patients were randomly assigned (high-dose MF-IND, n=445; medium-dose MF-IND, n=439; high-dose MF, n=442; medium-dose MF, n=444; high-dose FLU-SAL, n=446), of which 1973 (89·0%) completed the study treatment and 234 (10·6%) prematurely discontinued study treatment. High-dose MF-IND (treatment difference [Δ] 132 mL [95% CI 88 to 176]; p<0·001) and medium-dose MF-IND (Δ 211 mL [167 to 255]; p<0·001) showed superiority in improving trough FEV1 over corresponding MF doses from baseline at week 26. High-dose MF-IND was non-inferior to high-dose FLU-SAL in improving trough FEV1 from baseline at week 26 (Δ 36 mL [-7 to 80]; p=0·101). Overall, the incidence of adverse events was similar across the treatment groups.
CONCLUSIONS:Once-daily FDC of ICS and LABA (MF-IND) significantly improved lung function over ICS monotherapy (MF) at week 26; high-dose MF-IND was non-inferior to twice-daily combination of ICS and LABA (high-dose FLU-SAL) for improvement in trough FEV1. The combination of MF-IND provides a novel once-daily dry powder option for asthma control.
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