Weill Cornell Medical College, New York-Presbyterian Hospital/Weill Cornell Medical Center, 525 E 68th St, Room M-522, Box 130, New York, NY, 10065, USA.
Scottish Centre for Respiratory Research, Ninewells Hospital, University of Dundee, Dundee, Scotland, UK.
Respir Res. 2020 May 25;21(1):128. doi: 10.1186/s12931-020-01388-y.
The Phase III PINNACLE studies assessed the efficacy and safety of glycopyrrolate/formoterol fumarate metered dose inhaler (GFF MDI), a dual long-acting bronchodilator for chronic obstructive pulmonary disease (COPD). Here we present a pre-specified pooled analysis of PINNACLE-1, PINNACLE-2, and PINNACLE-4.
PINNACLE-1, -2, and -4 were multicenter, double-blind, randomized controlled trials that enrolled patients with moderate-to-very severe COPD, with no requirement for exacerbation history or a high symptom burden. Patients received GFF MDI 18/9.6 μg, glycopyrrolate (GP) MDI 18 μg, formoterol fumarate (FF) MDI 9.6 μg, or placebo MDI, twice-daily for 24 weeks. The primary endpoint of the pooled analysis was the change from baseline in morning pre-dose trough forced expiratory volume in 1 s (FEV) at week 24. Secondary endpoints included COPD exacerbations and clinically important deterioration (CID). Adverse events were also assessed.
The pooled intent-to-treat population included 4983 patients; of these, 61.9% had a COPD assessment test (CAT) score ≥15, and 25.0% had experienced ≥1 moderate/severe exacerbation in the past year. At week 24, GFF MDI improved morning pre-dose trough FEV versus GP MDI (least squares mean [LSM] difference [95% confidence interval (CI)]: 59 mL [43, 75]), FF MDI (65 mL [48, 81]), and placebo MDI (146 mL [125, 166]); all p < 0.0001. GFF MDI reduced the risk of a moderate/severe exacerbation by 18% (p = 0.0168), 15% (p = 0.0628), and 28% (p = 0.0012) compared with GP MDI, FF MDI, and placebo MDI, respectively. In general, exacerbation risk reduction with GFF MDI versus comparators was greater in subgroups of symptomatic patients (CAT ≥15) and those who had an exacerbation history, than in the pooled intent-to-treat population. The risk of CID was also lower with GFF MDI versus GP MDI (23% decrease), FF MDI (17%), and placebo MDI (49%); all p < 0.0001. All treatments were well tolerated, with no unexpected safety signals.
This pooled analysis of the PINNACLE studies demonstrated that GFF MDI improved lung function and reduced the risk of exacerbations compared with monocomponents and placebo in patients with COPD. Exacerbation reductions with GFF MDI versus comparators were generally greater in patients with higher symptom burden and those with exacerbation history.
ClinicalTrials.gov NCT01854645, NCT01854658, and NCT02343458. Registered 13 May 2013 (NCT01854645, NCT01854658) and 6 January 2015 (NCT02343458).
III 期 PINNACLE 研究评估了吡咯烷酮/福莫特罗富马酸盐定量吸入器（GFF MDI）的疗效和安全性，GFF MDI 是一种用于慢性阻塞性肺疾病（COPD）的双长效支气管扩张剂。这里我们报告了 PINNACLE-1、PINNACLE-2 和 PINNACLE-4 的预先指定的汇总分析。
PINNACLE-1、-2 和 -4 是多中心、双盲、随机对照试验，招募了中重度至重度 COPD 患者，没有恶化史或高症状负担的要求。患者接受 GFF MDI 18/9.6 μg、吡咯烷酮（GP）MDI 18 μg、福莫特罗富马酸盐（FF）MDI 9.6 μg 或安慰剂 MDI，每日两次，共 24 周。汇总分析的主要终点是第 24 周晨前谷用力呼气量（FEV）较基线的变化。次要终点包括 COPD 加重和临床重要恶化（CID）。还评估了不良事件。
汇总意向治疗人群包括 4983 名患者；其中，61.9%的患者 COPD 评估测试（CAT）评分≥15，25.0%的患者在过去一年中有≥1 次中度/重度加重。第 24 周，GFF MDI 与 GP MDI（最小二乘均值[LS 均值]差异[95%置信区间（CI）]：59mL[43，75]）、FF MDI（65mL[48，81]）和安慰剂 MDI（146mL[125，166]）相比，改善了晨前谷 FEV。所有 p 值均<0.0001。与 GP MDI、FF MDI 和安慰剂 MDI 相比，GFF MDI 分别降低了 18%（p=0.0168）、15%（p=0.0628）和 28%（p=0.0012）中度/重度加重的风险。一般来说，GFF MDI 与对照药物相比，在症状更严重的患者（CAT≥15）和有加重史的患者中，降低加重风险的效果更大，而在汇总意向治疗人群中则更小。与 GP MDI（23%减少）、FF MDI（17%）和安慰剂 MDI（49%）相比，GFF MDI 降低 CID 的风险也更低；所有 p 值均<0.0001。所有治疗均耐受良好，无意外安全信号。
这项 PINNACLE 研究的汇总分析表明，与单药成分和安慰剂相比，GFF MDI 改善了 COPD 患者的肺功能，降低了加重的风险。与对照药物相比，GFF MDI 降低加重的效果在症状负担较高的患者和有加重史的患者中通常更大。
ClinicalTrials.gov NCT01854645、NCT01854658 和 NCT02343458。2013 年 5 月 13 日（NCT01854645、NCT01854658）和 2015 年 1 月 6 日（NCT02343458）注册。
