一项 IIb 期随机、慢性剂量、不完全分组、交叉研究，比较了通过计量吸入器给予的格隆溴铵与安慰剂和活性对照药物在中重度 COPD 患者中的疗效。
A phase IIb randomized, chronic-dosing, incomplete block, cross-over study of glycopyrronium, delivered via metered dose inhaler, compared with a placebo and an active control in patients with moderate-to-severe COPD.
机构信息
Clinical Research Institute of Southern Oregon, Medford, OR, USA.
American Health Research, Charlotte, NC, USA.
出版信息
Respir Res. 2018 Mar 5;19(1):38. doi: 10.1186/s12931-018-0739-6.
BACKGROUND
Long-acting muscarinic antagonist (LAMA) and long-acting β-agonist (LABA) bronchodilators are key to the pharmacologic treatment of chronic obstructive pulmonary disease (COPD). This Phase IIb study investigated the safety and efficacy of four doses of the LAMA glycopyrronium (GP) delivered using co-suspension delivery technology via metered dose inhaler (MDI). The study was part of a wider clinical trial program performed to determine the optimal dose of GP MDI, the LABA formoterol fumarate dihydrate (FF) MDI, and glycopyrronium/formoterol fumarate dihydrate (GFF) MDI fixed-dose combination to be taken forward into Phase III studies.
METHODS
In this randomized, double-blind, 7-day chronic-dosing, three-period incomplete block, cross-over study, patients with moderate-to-severe COPD received two of the four doses of GP MDI (28.8 μg, 14.4 μg, 7.2 μg, and 3.6 μg) twice daily (BID), and either placebo MDI BID or open-label ipratropium MDI 34 μg four times daily. The primary efficacy endpoint was forced expiratory volume in 1 s (FEV) area under the curve from 0 to 12 h (AUC) relative to baseline on Day 7. Secondary and exploratory efficacy endpoints were assessed on Days 1 and 7. Safety and tolerability were evaluated throughout the study.
RESULTS
All GP MDI treatments were superior to placebo MDI for the primary efficacy endpoint (all p < 0.0001). However, only GP MDI 28.8 μg and 14.4 μg demonstrated statistical superiority to placebo MDI for all secondary efficacy endpoints analyzed in this study, with the exception of GP MDI 14.4 μg versus placebo MDI for the proportion of patients achieving ≥12% improvement in FEV. No nominally significant differences were observed between GP MDI 28.8 μg and GP MDI 14.4 μg for any of the endpoints. All doses of GP MDI were well tolerated, with no unexpected safety findings.
CONCLUSIONS
This study indicated that there was no advantage of GP MDI 28.8 μg compared with GP MDI 14.4 μg. It therefore added to the evidence from the Phase I/II clinical trial program, which identified GP MDI 14.4 μg as the most appropriate dose for use in the Phase III clinical studies.
TRIAL REGISTRATION
ClinicalTrials.gov (NCT01350128). Registered May 09, 2011.
背景
长效毒蕈碱拮抗剂（LAMA）和长效β-激动剂（LABA）支气管扩张剂是慢性阻塞性肺疾病（COPD）药物治疗的关键。这项 IIb 期研究调查了使用计量吸入器（MDI）共悬浮递送技术递送的四种剂量 LAMA 格隆溴铵（GP）的安全性和疗效。该研究是更广泛的临床试验计划的一部分，旨在确定 GP MDI、LABA 富马酸福莫特罗二水合物（FF）MDI 和格隆溴铵/富马酸福莫特罗二水合物（GFF）MDI 固定剂量组合的最佳剂量，这些药物将进入 III 期研究。
方法
在这项随机、双盲、为期 7 天的慢性给药、三周期不完全块、交叉研究中，中重度 COPD 患者每天两次（BID）接受四种剂量的 GP MDI（28.8μg、14.4μg、7.2μg 和 3.6μg）中的两种，或接受安慰剂 MDI BID 或开放标签异丙托溴铵 MDI 34μg，每日 4 次。主要疗效终点是第 7 天 0 至 12 小时（AUC）的用力呼气量（FEV）曲线相对于基线的变化（FEV）。次要和探索性疗效终点在第 1 天和第 7 天进行评估。整个研究期间评估安全性和耐受性。
结果
所有 GP MDI 治疗均优于安慰剂 MDI 对主要疗效终点（均 p<0.0001）。然而，只有 GP MDI 28.8μg 和 14.4μg 在本研究分析的所有次要疗效终点中显示出统计学优势，除了 GP MDI 14.4μg 与安慰剂 MDI 相比，FEV 改善 12%以上的患者比例外。在任何终点，GP MDI 28.8μg 与 GP MDI 14.4μg 之间均未观察到名义上的显著差异。所有剂量的 GP MDI 均具有良好的耐受性，未发现意外的安全性问题。
结论
这项研究表明，GP MDI 28.8μg 与 GP MDI 14.4μg 相比没有优势。因此，它增加了来自 I/II 期临床试验计划的证据，该计划确定 GP MDI 14.4μg 是用于 III 期临床试验的最合适剂量。
试验注册
ClinicalTrials.gov（NCT01350128）。2011 年 5 月 9 日注册。
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