三联单吸入器超细干粉治疗与长效抗胆碱能药物治疗慢性阻塞性肺疾病（TRINITY）：一项双盲、平行组、随机对照试验。
Single inhaler extrafine triple therapy versus long-acting muscarinic antagonist therapy for chronic obstructive pulmonary disease (TRINITY): a double-blind, parallel group, randomised controlled trial.
机构信息
Division of Infection, Immunity and Respiratory Medicine, University of Manchester, Manchester, UK; University Hospital South Manchester NHS Foundation Trust, Manchester, UK; Medicines Evaluation Unit, Manchester, UK.
Research Centre on Asthma and COPD, University of Ferrara, Ferrara, Italy.
出版信息
Lancet. 2017 May 13;389(10082):1919-1929. doi: 10.1016/S0140-6736(17)30188-5. Epub 2017 Apr 3.
BACKGROUND
Limited data are available for the efficacy of triple therapy with two long-acting bronchodilators and an inhaled corticosteroid in chronic obstructive pulmonary disease (COPD). We compared treatment with extrafine beclometasone dipropionate, formoterol fumarate, and glycopyrronium bromide (BDP/FF/GB; fixed triple) with tiotropium, and BDP/FF plus tiotropium (open triple).
METHODS
For this double-blind, parallel-group, randomised, controlled trial, eligible patients had COPD, post-bronchodilator forced expiratory volume in 1 s (FEV) of less than 50%, at least one moderate-to-severe COPD exacerbation in the previous 12 months, and a COPD Assessment Test total score of at least 10. After a 2-week run-in period receiving one inhalation per day via single-dose dry-powder inhaler of open-label 18 μg tiotropium, patients were randomised (2:2:1) using a interactive response technology system to 52 weeks treatment with tiotropium, fixed triple, or open triple. Randomisation was stratified by country and severity of airflow limitation. The primary endpoint was moderate-to-severe COPD exacerbation rate. The key secondary endpoint was change from baseline in pre-dose FEV at week 52. The trial is registered with ClinicalTrials.gov, number NCT01911364.
FINDINGS
Between Jan 21, 2014, and March 18, 2016, 2691 patients received fixed triple (n=1078), tiotropium (n=1075), or open triple (n=538). Moderate-to-severe exacerbation rates were 0·46 (95% CI 0·41-0·51) for fixed triple, 0·57 (0·52-0·63) for tiotropium, and 0·45 (0·39-0·52) for open triple; fixed triple was superior to tiotropium (rate ratio 0·80 [95% CI 0·69-0·92]; p=0·0025). For week 52 pre-dose FEV, fixed triple was superior to tiotropium (mean difference 0·061 L [0·037 to 0·086]; p<0·0001) and non-inferior to open triple (-0·003L [-0·033 to 0·027]; p=0·85). Adverse events were reported by 594 (55%) patients with fixed triple, 622 (58%) with tiotropium, and 309 (58%) with open triple.
INTERPRETATION
In our TRINITY study, treatment with extrafine fixed triple therapy had clinical benefits compared with tiotropium in patients with symptomatic COPD, FEV of less than 50%, and a history of exacerbations.
FUNDING
Chiesi Farmaceutici SpA.
背景
在慢性阻塞性肺疾病（COPD）中，两种长效支气管扩张剂和吸入性皮质类固醇三联疗法的疗效数据有限。我们比较了布地奈德福莫特罗格隆溴铵（BDP/FF/GB；固定三联）和噻托溴铵以及 BDP/FF 加噻托溴铵（开放三联）的治疗效果。
方法
这项双盲、平行组、随机、对照试验纳入了符合条件的 COPD 患者，这些患者支气管扩张剂后用力呼气量 1 秒（FEV）<50%，在过去 12 个月中至少有一次中度至重度 COPD 加重，且 COPD 评估测试总分为至少 10 分。在接受为期 2 周的单剂量干粉吸入器开放标签 18 μg 噻托溴铵每日一次的预治疗期后，患者使用交互式反应技术系统按 2:2:1 的比例随机分配（分层因素为国家和气流受限严重程度），接受 52 周的噻托溴铵、固定三联或开放三联治疗。随机分组的依据是治疗药物和治疗方案。主要终点是中度至重度 COPD 加重的发生率。关键次要终点是治疗 52 周时预剂量 FEV 的变化。该试验在 ClinicalTrials.gov 注册，编号为 NCT01911364。
结果
在 2014 年 1 月 21 日至 2016 年 3 月 18 日期间，共有 2691 名患者接受了固定三联（n=1078）、噻托溴铵（n=1075）或开放三联（n=538）治疗。固定三联的中度至重度加重发生率为 0.46（95%CI 0.41-0.51），噻托溴铵为 0.57（0.52-0.63），开放三联为 0.45（0.39-0.52）；固定三联优于噻托溴铵（发生率比 0.80[95%CI 0.69-0.92]；p=0.0025）。对于第 52 周的预剂量 FEV，固定三联优于噻托溴铵（平均差值 0.061 L[0.037 至 0.086]；p<0.0001），与开放三联非劣效（差值 0.003 L[-0.033 至 0.037]；p=0.85）。594（55%）名接受固定三联治疗的患者、622（58%）名接受噻托溴铵治疗的患者和 309（58%）名接受开放三联治疗的患者报告了不良事件。
结论
在我们的 TRINITY 研究中，与噻托溴铵相比，布地奈德福莫特罗格隆溴铵固定三联疗法在有症状的 COPD、FEV<50%和有加重史的患者中具有临床获益。
资金来源
Chiesi Farmaceutici SpA。
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