BACKGROUND:The drug development process can be streamlined by combining the traditionally separate stages of dose-finding (Phase IIb) and confirmation of efficacy and safety (Phase III) using an adaptive seamless design. This approach was used in a clinical study of indacaterol, a novel once-daily (od) inhaled long-acting beta(2)-adrenoreceptor agonist bronchodilator for the treatment of COPD (chronic obstructive pulmonary disease). METHODS:The study comprised a dose-finding stage with dose selection after 14 days of treatment, and a second stage evaluating efficacy and safety during 26 weeks of treatment. The dose-finding stage included seven randomized treatment arms: double-blind indacaterol 75 microg, 150 microg, 300 microg or 600 microg od, the beta(2)-adrenoceptor agonist formoterol 12 microg twice-daily or placebo, or the anticholinergic tiotropium 18 microg od open-label. An independent data monitoring committee selected two indacaterol doses based on unblinded results of an interim analysis performed by an independent statistician. The sponsor, investigators and patients remained blinded to the results. The indacaterol doses were selected using pre-set efficacy criteria for trough (24-h post-dose) and early (1-4 h post-dose) bronchodilator effect after 14 days, and all safety data. To qualify for selection, the doses had to exceed a threshold for clinical relevance or be superior to either tiotropium or formoterol, whichever was the highest value. Selected doses were continued into the second, 26-week stage. The two other indacaterol doses not selected, and formoterol, were discontinued following dose selection. RESULTS:801 patients with moderate-to-severe COPD were evaluated. Indacaterol 150 microg was the lowest effective dose, exceeding criteria for trough FEV(1) (reference value 140 mL vs placebo) and FEV(1) AUC(1-4 h) (reference value 220 mL vs placebo). No safety signal was observed with any dose of indacaterol. Thus, indacaterol 150 and 300 microg were selected to continue into the second, 26-week stage. CONCLUSION:The adaptive seamless design is a novel and efficient way to combine dose selection with efficacy evaluation and safety confirmation in a single trial.

译文

背景:通过将传统上独立的剂量确定阶段(阶段IIb)和使用适应性无缝设计确认疗效和安全性(阶段III)相结合,可以简化药物开发过程。这种方法被用于茚达特罗的临床研究,茚达特罗是一种新型的每日一次(od)吸入的长效β(2)-肾上腺素能受体激动剂支气管扩张药,用于治疗COPD(慢性阻塞性肺疾病)。
方法:该研究包括在治疗14天后进行剂量选择的剂量确定阶段,以及在治疗26周期间评估疗效和安全性的第二阶段。剂量确定阶段包括七个随机治疗组:双盲茚达特罗75微克,150微克,300微克或600微克od,β(2)-肾上腺素受体激动剂福莫特罗每天两次或安慰剂12微克,或抗胆碱噻托溴铵18 microg od开放标签。一个独立的数据监控委员会根据独立统计学家进行的中期分析的非盲结果选择了两种茚达特罗剂量。申办者,研究者和患者对结果不知情。茚达特罗的剂量是根据预先设定的药效标准(14天后的药谷(给药后24小时)和早期(给药后1-4小时))和所有安全性数据选择的。为了符合选择条件,剂量必须超过临床相关性阈值或优于噻托溴铵或福莫特罗,以二者中的最高值为准。选择的剂量持续到第二个26周阶段。选择剂量后,中止未选择的另外两种茚达特罗剂量和福莫特罗。
结果:对801例中重度COPD患者进行了评估。 150克茚达特罗是最低有效剂量,超过谷值FEV(1)(参考值140毫升,相对于安慰剂)和FEV(1)AUC(1-4小时)(参考值220毫升,相对于安慰剂)。任何剂量的茚达特罗均未观察到安全性信号。因此,选择茚达特罗150和300微克继续进入第二个26周阶段。
结论:自适应无缝设计是在单一试验中将剂量选择与疗效评估和安全性确认相结合的一种新颖而有效的方法。

+1
+2
100研值 100研值 ¥99课程
检索文献一次
下载文献一次

去下载>

成功解锁2个技能,为你点赞

《SCI写作十大必备语法》
解决你的SCI语法难题!

技能熟练度+1

视频课《玩转文献检索》
让你成为检索达人!

恭喜完成新手挑战

手机微信扫一扫,添加好友领取

免费领《Endnote文献管理工具+教程》

微信扫码, 免费领取

手机登录

获取验证码
登录